Nanomaterial‐Mediated Modulation of TRPV1 Ion Channels for Biomedical Applications

✅ 全文

纳米材料介导的TRPV1离子通道调控及其生物医学应用

作者 Peng Pei; Yafei Du; Jiong‐Wei Wang; Xiaogang Liu 期刊 Advanced Materials Technologies 发表日期 2024 ISSN 2365-709X DOI 10.1002/admt.202401355 类型原创研究 (Original Research)

📄 英文摘要 English Abstract

Abstract Transient receptor potential vanilloid subtype 1 (TRPV1) is a nonselective cation channel involved in various physiological processes such as pain perception, thermoregulation, and inflammatory responses. Nanomaterials have emerged as precise tools to modulate TRPV1 activity, offering high spatiotemporal resolution and specificity. These nanomaterials act as transducers, responding to internal or external stimuli such as pH, light, electric, and magnetic fields to deliver modulatory agents like agonists, antagonists, heat, reactive species, and mechanical forces to TRPV1 channels. This strategy enables non‐invasive and targeted therapeutic interventions for diseases associated with TRPV1 dysfunction. In this review, recent advances are highlighted in nanomaterial‐mediated TRPV1 modulation and its biomedical applications. The TRPV1 structure and activation mechanisms, the integration of nanomaterials for effective TRPV1 modulation, and the required material properties are covered. Moreover, biomedical applications are discussed, including neurostimulation, neurological disorder therapies, cancer therapies, metabolic disease treatments, and cardiovascular disease interventions. Future research directions and challenges in this field are also proposed.

📄 中文摘要 Chinese Abstract

中文

瞬时受体电位香草酸亚型1（TRPV1）是一种非选择性阳离子通道，参与多种生理过程，如疼痛感知、体温调节和炎症反应。纳米材料已成为精确调控TRPV1活性的工具，具有高时空分辨率和特异性。这些纳米材料作为换能器，响应pH、光、电场和磁场等内部或外部刺激，向TRPV1通道递送激动剂、拮抗剂、热量、活性物种和机械力等调节剂。该策略能够实现对TRPV1功能障碍相关疾病的无创和靶向治疗干预。 TRPV1于1997年由David Julius及其同事从大鼠背根神经节中克隆，促进Ca2+、Na+和Mg2+的内流，可被多种物理和化学刺激激活，如激动剂、有害热（≥42°C）、质子以及活性氧和活性氮物种。尽管TRPV1主要分布于与疼痛感知相关的初级感觉神经元中，但它也在膀胱、胰腺和睾丸等非神经元细胞中表达，提示其具有更广泛的生理意义。鉴于TRPV1参与众多生理和病理过程，它已成为多种疾病的有前景的治疗靶点，包括癌症、神经退行性疾病、心血管疾病和疼痛管理。

📋 英文结构化总结 English Structured Summary

全文整理

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Background Transient receptor potential vanilloid subtype 1 (TRPV1) is a nonselective cation channel involved in various physiological processes such as pain perception, thermoregulation, and inflammatory responses. Nanomaterials have emerged as precise tools to modulate TRPV1 activity, offering high spatiotemporal resolution and specificity. These nanomaterials act as transducers, responding to internal or external stimuli such as pH, light, electric, and magnetic fields to deliver modulatory agents like agonists, antagonists, heat, reactive species, and mechanical forces to TRPV1 channels. This strategy enables non-invasive and targeted therapeutic interventions for diseases associated with TRPV1 dysfunction.

TRPV1, first cloned from rat dorsal root ganglia by David Julius and colleagues in 1997, facilitates the influx of Ca2+, Na+, and Mg2+, and can be activated by various physical and chemical stimuli such as agonists, noxious heat (≥42 °C), protons, and reactive oxygen and nitrogen species. Although TRPV1 is mainly distributed in primary sensory neurons associated with pain perception, it is also expressed in non-neuronal cells in organs such as the urinary bladder, pancreas, and testis, suggesting its broader physiological significance. Given its involvement in numerous physiological and pathological processes, TRPV1 has emerged as a promising therapeutic target for various disorders, including cancer, neurodegenerative diseases, cardiovascular diseases, and pain management.

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Methods N/A - Review article

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Results Functional nanomaterials have emerged as effective tools for precisely modulating TRPV1 signaling pathways with high spatiotemporal resolution and specificity, particularly within deep tissues. These nanomaterials can act as transducers that respond to internal or external stimuli such as pH, light, electric, and magnetic fields to precisely release or generate activators required for TRPV1 activation. For example, lipid nanoparticles can locally deliver capsaicin to activate TRPV1 while minimizing toxicity. Photothermal nanomaterials such as gold nanorods can rapidly activate TRPV1 using near-infrared (NIR) light. However, the limited penetration of NIR light into tissues restricts its clinical application. Alternatively, magnetic nanomaterials such as Fe3O4 nanoparticles and ferritin can activate TRPV1 through heat or magnetic force in response to alternating magnetic fields, effectively targeting deep tissues. Nevertheless, the process of magnetothermal generation is slow, often requiring tens to thousands of seconds to elicit a Ca2+ influx, which exceeds the temporal dynamics of neuronal firing.

The review covers biomedical applications including neurostimulation, neurological disorder therapies (e.g., Parkinson’s disease), cancer therapies (e.g., immunotherapy), treatment of metabolic diseases, and cardiovascular disease interventions (e.g., atherosclerosis). Future research directions and challenges in this field are also proposed.

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Data Summary The review reports specific quantitative parameters: TRPV1 is activated by noxious heat at ≥42 °C; magnetothermal generation using Fe3O4 nanoparticles or ferritin requires tens to thousands of seconds to elicit Ca2+ influx. No other quantitative results or key statistics are presented in the provided text; the review summarizes qualitative findings from the literature on nanomaterial-mediated TRPV1 modulation.

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Conclusions In this review, recent advances are highlighted in nanomaterial-mediated TRPV1 modulation and its biomedical applications. The TRPV1 structure and activation mechanisms, the integration of nanomaterials for effective TRPV1 modulation, and the required material properties are covered. Nanomaterials enable non-invasive, targeted therapeutic interventions for diseases linked to TRPV1 dysfunction. Future research directions and challenges in this emerging field are also proposed.

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Practical Significance The nanomaterial-mediated modulation of TRPV1 channels has real-world applications in precise neurostimulation and therapeutics for neurological disorders such as Parkinson’s disease, cancer therapies such as immunotherapy, treatment of metabolic diseases, as well as treatment of cardiovascular diseases like atherosclerosis. This approach offers non-invasive, targeted interventions with high spatiotemporal resolution and specificity for conditions associated with TRPV1 dysfunction.

📋 中文结构化总结 Chinese Structured Summary

中文

背景:

TRPV1于1997年由David Julius及其同事从大鼠背根神经节中克隆，促进Ca2+、Na+和Mg2+的内流，可被多种物理和化学刺激激活，如激动剂、有害热（≥42°C）、质子以及活性氧和活性氮物种。尽管TRPV1主要分布于与疼痛感知相关的初级感觉神经元中，但它也在膀胱、胰腺和睾丸等非神经元细胞中表达，提示其具有更广泛的生理意义。鉴于TRPV1参与众多生理和病理过程，它已成为多种疾病的有前景的治疗靶点，包括癌症、神经退行性疾病、心血管疾病和疼痛管理。

方法:

不适用——综述文章

结果:

功能纳米材料已成为精确调控TRPV1信号通路的有效工具，具有高时空分辨率和特异性，尤其在深层组织中。这些纳米材料可作为换能器，响应pH、光、电场和磁场等内部或外部刺激，精确释放或产生TRPV1激活所需的激活剂。例如，脂质纳米颗粒可在局部递送辣椒素以激活TRPV1，同时最小化毒性。光热纳米材料如金纳米棒可利用近红外（NIR）光快速激活TRPV1。然而，NIR光在组织中的穿透深度有限，限制了其临床应用。或者，磁性纳米材料如Fe3O4纳米颗粒和铁蛋白可通过热量或磁力在交变磁场作用下激活TRPV1，有效靶向深层组织。然而，磁热产生过程缓慢，通常需要数十至数千秒才能引发Ca2+内流，这超过了神经元放电的时间动态范围。

本综述涵盖了生物医学应用，包括神经刺激、神经系统疾病治疗（如帕金森病）、癌症治疗（如免疫疗法）、代谢性疾病治疗以及心血管疾病干预（如动脉粥样硬化）。还提出了该领域的未来研究方向和挑战。

数据总结:

本综述报告了具体的定量参数：TRPV1在≥42°C的有害热下被激活；使用Fe3O4纳米颗粒或铁蛋白的磁热产生需要数十至数千秒才能引发Ca2+内流。所提供的文本中没有呈现其他定量结果或关键统计数据；本综述总结了纳米材料介导TRPV1调控的文献中的定性发现。

结论:

在本综述中，重点介绍了纳米材料介导的TRPV1调控及其生物医学应用的最新进展。涵盖了TRPV1结构和激活机制、纳米材料整合以实现有效TRPV1调控以及所需的材料特性。纳米材料能够实现对TRPV1功能障碍相关疾病的无创、靶向治疗干预。还提出了这一新兴领域的未来研究方向和挑战。

实际意义:

纳米材料介导的TRPV1通道调控在精确神经刺激和神经系统疾病（如帕金森病）治疗、癌症治疗（如免疫疗法）、代谢性疾病治疗以及心血管疾病（如动脉粥样硬化）治疗方面具有实际应用价值。该方法为TRPV1功能障碍相关疾病提供了具有高时空分辨率和特异性的无创、靶向干预手段。

📖 英文全文 English Full Text

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Nanomaterial-Mediated Modulation of TRPV1 Ion Channels for Biomedical Applications Peng Pei, Yafei Du, Jiong-Wei Wang,* and Xiaogang Liu*

Transient receptor potential vanilloid channels (TRPV1-6) are polymodal transmembrane proteins predominantly located on the plasma membrane of various cell types and tissues. These

channels are essential for physiological processes such as sensory perception, pain sensation, thermoregulation, and cellular homeostasis.[1] Among them, TRPV1, ﬁrst cloned from rat dorsal root ganglia by David Julius and colleagues in 1997, has attracted much attention.[2] As a nonselective cation channel, TRPV1 facilitates the inﬂux of Ca2+ , Na+ , and Mg2+ , and can be activated by various physical and chemical stimuli such as agonists,[2,3] noxious heat (≥42 °C),[4] protons,[5] and reactive oxygen and nitrogen species.[6] Although TRPV1 is mainly distributed in primary sensory neurons associated with pain perception,[5,7] it is also expressed in non-neuronal cells in organs such as the urinary bladder, pancreas, and testis, suggesting its broader physiological signiﬁcance.[8] The modulation of TRPV1 is complex and varies depending on its tissue location and speciﬁc physiological or pathological context. This sensitization by diverse agonists involves intricate regulatory mechanisms that inﬂuence its function across diﬀerent scenarios. Given its involvement in numerous physiological and pathological processes, TRPV1 has emerged as a promising therapeutic target for various disorders, including cancer, neurodegenerative diseases,

P. Pei, J.-W. Wang, X. Liu Department of Surgery Yong Loo Lin School of Medicine National University of Singapore 1E Kent Ridge Road, Singapore 119228, Singapore E-mail: surwang@nus.edu.sg; chmlx@nus.edu.sg P. Pei, Y. Du, X. Liu Department of Chemistry National University of Singapore Singapore 117543, Singapore P. Pei, J.-W. Wang, X. Liu Nanomedicine Translational Research Programme Yong Loo Lin School of Medicine National University of Singapore Singapore 117609, Singapore

Y. Du Institute of Molecular and Cell Biology (IMCB) Agency for Science Technology and Research (A∗STAR) 61 Biopolis Drive, Proteos, Singapore 138673, Singapore J.-W. Wang Cardiovascular Research Institute Yong Loo Lin School of Medicine National University of Singapore 14 Medical Drive, Singapore 117599, Singapore J.-W. Wang Departmeng of Physiology Yong Loo Lin School of Medicine National University of Singapore 2 Medical Drive, Singapore 117593, Singapore

Transient receptor potential vanilloid subtype 1 (TRPV1) is a nonselective cation channel involved in various physiological processes such as pain perception, thermoregulation, and inﬂammatory responses. Nanomaterials have emerged as precise tools to modulate TRPV1 activity, oﬀering high spatiotemporal resolution and speciﬁcity. These nanomaterials act as transducers, responding to internal or external stimuli such as pH, light, electric, and magnetic ﬁelds to deliver modulatory agents like agonists, antagonists, heat, reactive species, and mechanical forces to TRPV1 channels. This strategy enables non-invasive and targeted therapeutic interventions for diseases associated with TRPV1 dysfunction. In this review, recent advances are highlighted in nanomaterial-mediated TRPV1 modulation and its biomedical applications. The TRPV1 structure and activation mechanisms, the integration of nanomaterials for eﬀective TRPV1 modulation, and the required material properties are covered. Moreover, biomedical applications are discussed, including neurostimulation, neurological disorder therapies, cancer therapies, metabolic disease treatments, and cardiovascular disease interventions. Future research directions and challenges in this ﬁeld are also proposed.

The ORCID identiﬁcation number(s) for the author(s) of this article can be found under https://doi.org/10.1002/admt.202401355 DOI: 10.1002/admt.202401355 Adv. Mater. Technol. 2024, 2401355 2401355 (1 of 20)

Figure 1. Nanomaterial-mediated TRPV1 modulation for biomedical applications. In general, rationally designed nanomaterials can act as transducers that respond to speciﬁc internal or external stimuli to locally release or generate activators required to activate TRPV1 channels, thus functioning in various biomedical applications associated with TRPV1 dysfunction.

cardiovascular diseases, and pain management. Over the past decade, functional nanomaterials have emerged as eﬀective tools for precisely modulating TRPV1 signaling pathways with high spatiotemporal resolution and speciﬁcity,[9] particularly within deep tissues. These nanomaterials can act as transducers that respond to internal or external stimuli such as pH, light, electric, and magnetic ﬁelds to precisely release or generate activators required for TRPV1 activation. This approach oﬀers non-invasive, targeted therapeutic interventions for diseases linked to TRPV1 dysfunction. The selection and optimization of nanomaterials are crucial for achieving precise and eﬃcient TRPV1 activation. For example, lipid nanoparticles can locally deliver capsaicin to activate TRPV1 while minimizing toxicity.[10] Photothermal nanomaterials such as gold nanorods can rapidly activate TRPV1 using near-infrared (NIR) light.[11] However, the limited penetration of NIR light into tissues restricts its clinical application.[12] Alternatively, magnetic nanomaterials such as Fe3 O4 nanoparticles and ferritin can activate TRPV1 through heat or magnetic force in response to alternating magnetic ﬁelds, eﬀectively targeting deep tissues.[13] Nevertheless, the process of magnetothermal generation is slow, often requiring tens to thousands of seconds to elicit a Ca2+ inﬂux, which exceeds the temporal dynamics of neuronal ﬁring. In this review, we aim to summarize the strategies for nanomaterial-mediated TRPV1 modulation and their biomedi- Adv. Mater. Technol. 2024, 2401355

cal applications (Figure 1). We ﬁrst introduce various activators responsible for gating TRPV1 channels and their respective mechanisms. We then highlight the integration of nanomaterials with TRPV1 modulation, focusing on the material properties required for eﬃcient TRPV1 activation in diﬀerent scenarios. We explore the biomedical applications of nanomaterial-mediated TRPV1 modulation, including precise neurostimulation and therapeutics for neurological disorders such as Parkinson’s disease, cancer therapies such as immunotherapy, treatment of metabolic diseases, as well as treatment of cardiovascular diseases like atherosclerosis. Finally, we discuss the challenges and possible solutions in the emerging ﬁeld of nanomaterialmediated TRPV1 modulation.

2. Mechanisms of TRPV1 Activation The TRPV1 channel has a tetrameric structure with each subunit consisting of several domains (Figure 2a): the N-terminal domain (including the ankyrin repeat domain), the transmembrane domain, the TRP domain, and the C-terminal domain.[14] The transmembrane domain contains a voltage-gated like domain (S1–S4) and a pore domain (S5,S6). Notably, the pore domain consists of an “inverted teepee” structure near the extracellular side, which constitutes the selectivity ﬁlter, and an interleaved structure near the intracellular side, which forms the lower

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Figure 2. Structure and activation mechanism of the TRPV1 channel. a) Ribbon diagram showing a view of the TRPV1 monomer denoting speciﬁc domains (left), and topology depicting major structural domains in a TRPV1 subunit (right). Reproduced with permission from ref. [14b]. Copyright 2013 Springer Nature. b) Schematic of the main activation signals and key amino acid positions of the TRPV1 channel. Colored spheres represent various activators of the TRPV1 channel, with their positions corresponding to speciﬁc amino acid sites. For example, the red sphere indicates that capsaicin and RTX act on the same amino acid positions, including S513, Y512, and T551. The action sites are identiﬁed from TRPV1 channels in diﬀerent species: mouse (S513, Y512, T551, and E571), rat (V518, M547, I559, E600, C616, C621, N628, T633, E648, F649, N652, Y653, A657, F659, F660, E692, E701, and T704), chicken (C772 and C783), and human (C258 and C742).

gate. Upon activation, both selectivity ﬁlter and lower gate of TRPV1 can uniquely dilate to a wider size to allow ions such as Ca2+ and Na+ to pass through the channel. In this section, we introduce diﬀerent activators that gate TRPV1 channels, including exogenous and endogenous agonists, heat, and protons, along with the mechanisms by which they operate. To provide a clear and intuitive understanding, we have drawn a schematic diagram illustrating the main activation signals and key amino acid positions of the TRPV1 channel (Figure 2b).

2.1. Exogenous and Endogenous Agonists There are numerous exogenous and endogenous agonists that bind to key amino acids on TRPV1, initiating various signaling cascades. Exogenous agonists include both natural and synthetic chemicals, such as capsaicin and its analogues, piperine,[15]

Adv. Mater. Technol. 2024, 2401355 eugenol,[16] and gingerol,[17] resiniferatoxin,[2] and double-knot toxin.[18] Capsaicin, the pungent component of chili peppers, was the ﬁrst identiﬁed TRPV1 channel-speciﬁc agonist.[2] TRPV1 exhibits high selectivity (not activating TRPV2-6) and sensitivity (EC50 approximately sub-micromolar) toward capsaicin.[2,19] Upon activation by capsaicin, nociceptive neurons undergo a rapid inﬂux of Ca2+ and Na+ , leading to cell depolarization, action potential generation, and the sensation of spiciness.[2] Studies have identiﬁed speciﬁc action sites on TRPV1 for capsaicin, including Y512, S513, T551, E571, and the S4–S5 linker.[19,20] Capsazepine, the ﬁrst TRPV1 antagonist, inhibits channel opening by competitively binding to the same site as capsaicin.[21] Capsaicin analogs such as resiniferatoxin (RTX) also activate TRPV1, signiﬁcantly impacting thermoregulation and neurogenic inﬂammation.[2] These analogs display potency levels surpassing capsaicin by 3–4 orders of magnitude.[22] Mutagenesis

www.advancedsciencenews.com www.advmattechnol.de studies have identiﬁed residues Y511, S512, M547, and T550 as responsive to vanillin ligands. Moreover, spider toxins with structurally analogous sequences, such as double-knot toxin (DkTx), have been shown to interact with TRPV1. In the activated state, two divalent DkTx molecules are involved in this interaction,[18,23] with key residues crucial for sensitivity including I599, F649, A657, and F659.[17] Besides exogenous agonists, endogenous ligands of TRPV1 have been identiﬁed, such as bradykinin,[3a] adenosine triphosphate,[24] nerve growth factor,[3a] anandamide,[3b] arachidonic acid metabolites,[3c] and lipoxygenase products.[3d] These endogenous regulators play a crucial role in inﬂammation and nociception but generally exhibit low potency and require high activation thresholds. Under pathological conditions, endogenous regulators can synergistically activate TRPV1, highlighting their importance in physiological responses. For instance, bradykinin can bind to G protein-coupled receptors, particularly the B2 receptor, and activate protein kinase C through a signaling cascade. This activation leads to the phosphorylation of TRPV1, making it more sensitive to other stimuli such as heat, protons, and capsaicin.[3a,25] Similarly, anandamide interacts with speciﬁc residues (Y511, S512, Y554, and Y555), promoting Ca2+ inﬂux. This interaction sensitizes TRPV1 by activating both protein kinase A and C signaling cascades.[26]

2.2. Heat Activation TRPV1 can be activated by heat stimuli above 42 °C,[4] exhibiting high temperature sensitivity with a Q10 value of approximately 25, compared to the range of 2 to 3 for general temperature-sensitive ion channels.[2,27] The eﬃcacy of heat stimulation in activating the TRPV1 channel is ≈25% that of capsaicin, with generated action potentials showing a preference for Ca2+ and Mg2+ ions.[28] Experiments changing or recombining the membrane composition of artiﬁcial systems containing TRPV1 conﬁrmed its intrinsic temperature sensitivity.[29] Activation dynamics research indicated that temperature primarily regulates the opening rate of TRPV1.[4,29a,30] Temperature sensing structures are believed to be located at the N and C terminus,[31] the pore domain,[14a,32] the pore turret,[33] and the pore loop.[34] For instance, the exchange of C-terminal regions between TRPV1 and TRPM8 channels switched their sensitivity, indicating the importance of this region in thermal activation.[31b] Altering the domain between TRPV1 and TRPV2 revealed the crucial role of the N-terminal region of the ankyrin repeat domain in connecting the initial transmembrane segment for the temperature sensitivity.[29b] Additionally, the integrity of the TRP domain is crucial for eﬀective gating, with residues E692, R701, and T704 playing an important role in TRPV1 activity.[27a] Despite extensive research, the speciﬁc sites that initiate the temperature response in TRPV1 remain unidentiﬁed.

sensitive to other agonists by lowering the activation threshold, resulting in hyperalgesia.[2,36] For instance, the half-maximum effective pH value for proton activation is 5.4 at 22 °C, and current intensity induced by proton activation is ≈20%-30% of that generated by saturated capsaicin activation.[28] Proton activation of TRPV1 channel involves speciﬁc amino acids.[28,37] E600 is associated with proton potentiation, and E648 is a potential direct activation site.[38] In the apo structure, E600 forms a salt bridge with R455 from the neighboring subunit. Low pH exposure causes the side chain of E600 to rotate away from R455, disrupting the interaction and potentially leading to protonation of E648, transforming the pore ring to an open conformation. Mutations at E648 can speciﬁcally eliminate proton-induced activation without aﬀecting responses to other stimuli such as capsaicin and heat. In addition, single-residue mutations at the T633, V538, or F660 domains can eliminate the proton-induced currents while preserving capsaicin and heat activation.[39] 2.4. Oxidative Stress Activation Oxidative stress can activate or sensitize TRPV1 channels, leading to hyperalgesia. Reactive oxygen species (ROS), including hydrogen peroxide (H2 O2 ), superoxide (O2− ), hydroxyl radical (·OH), and singlet oxygen (1 O2 ), are most common in this process.[40] The redox state of TRPV1 is crucial in regulating its activity. Both reducing agents like dithiothreitol[41] and oxidants such as diamide, Cu:Phe, chloramine-T, and H2 O2 [42] enhance TRPV1 activity. Covalent modiﬁcation of cysteine, particularly by disulﬁde bonds between subunits, underlies the oxidative sensitization of TRPV1. Point mutagenesis studies identiﬁed C621 in rats, C772 and C783 in chicken as key sites for oxidative stress aﬀecting TRPV1 activity.[42b] Human TRPV1 has unique intercysteine subunit disulﬁde bonds, primarily established via C258 and C742, contributing signiﬁcantly to channel stability.[43] 2.5. Nitric Oxide Activation Nitric oxide (NO) serves as a key gaseous signaling molecule with swift diﬀusion capabilities, intricately engaged in diverse physiological functions, spanning neurotransmission, cardiovascular homeostasis, and immune responses.[44] NO can activate the TRPV1 channel through cysteine S-nitrosylation, leading to Ca2+ inﬂux and increased TRPV1 sensitivity to heat and protons.[6c] Mutations at C616 and C621 within TRPV1 result in notable inhibition of NO stimulation.[6c] NO can activate cultured primary DRG neurons and TRPV1-expressing CHO cells, while the broad-spectrum TRP channel antagonist ruthenium red can completely block the NO-induced activation current.[45] In addition, studies on electrical signals from CA1 pyramidal neurons using TRPV1 agonists and NO inhibitors conﬁrmed the eﬀect of NO on TRPV1-mediated neuronal signaling in the hippocampus.[46]

2.3. Proton Activation Similar to acid-sensitive ion channels (ASICs), TRPV1 can be activated by low extracellular pH levels (<6.0) at normal physiological temperatures.[28,35] This acidity can also make TRPV1 more

Adv. Mater. Technol. 2024, 2401355

3. Nanomaterials for TRPV1 Modulation Due to the diverse activation modalities of TRPV1, a variety of nanomaterials can be employed to modulate TRPV1 functionality 2401355 (4 of 20) © 2024 Wiley-VCH GmbH

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Figure 3. Integration of nanomaterials with TRPV1 modulation. Capsaicin-based nanomaterials activate TRPV1 channels by delivering capsaicin or controlling its release in response to stimuli such as light, heat, and acid. Photothermal nanomaterials generate local heat to activate TRPV1 channels in response to external light, while magnetothermal nanomaterials do the same in response to magnetic ﬁelds. In addition, certain nanomaterials can activate TRPV1 channels by producing nitric oxide through electrochemical reactions or by generating ROS or mechanical forces in response to magnetic ﬁelds. To enhance the activation eﬃciency of TRPV1 channels, it is crucial to optimize the properties of nanomaterials, including biocompatibility, targeting ability, magnetothermal and photothermal eﬀects, the wavelength of excitation light.

and associated physiological processes. Based on their activation mechanisms and triggering modes, we classify nanomaterials that activate TRPV1 into four distinct categories: capsaicin-based nanomaterials, photothermal nanomaterials, magnetothermal nanomaterials, and other nanomaterials associated with force, ROS and NO. These classiﬁcations encompass a wide range of material compositions, including small organic molecules, polymers, metals, and inorganic nanoparticles. In this section, we highlight the integration of nanomaterials with TRPV1 modulation and discuss the material properties required for eﬃcient TRPV1 activation (Figure 3).

3.1. Capsaicin-Based Nanomaterials Over the past two decades, capsaicin, a foremost TRPV1 agonist, has shown high sensitivity in activating TRPV1 channels, promising diverse applications such as cancer therapy and neurostimulation. However, its inherent hydrophobicity hampers effective distribution in the body, leading to potential systemic toxicity at elevated doses. The development of nanomedicine offers new opportunities to enhance the bioactivity of therapeutic

Adv. Mater. Technol. 2024, 2401355 capsaicin, prolong its bioavailability, and reduce its side eﬀects (Table 1).[47] Lipid nanoparticles, typically composed of ionizable lipids, helper lipids, cholesterol, and polyethylene glycol (PEG)-lipids, have emerged as a promising platform for drug delivery. They oﬀer protection against degradation and enhanced cellular uptake.[48] This has garnered signiﬁcant attention, particularly after the success of recent COVID-19 mRNA vaccines. Lipid nanoparticles have recently been favored as an ideal delivery system for capsaicin.[10,49] By optimizing components and preparation methods, these nanoparticles eﬃciently encapsulate capsaicin with adjustable size and exhibit good stability and biocompatibility.[10a,49a,b] Surface modiﬁcation further enhances the targeting ability of capsaicin-loaded nanoparticles to speciﬁc tissues. For instance, Lv et al. developed folic acid-conjugated lipid nanoparticles to actively target capsaicin to ovarian cancer cells,[10b] enhancing uptake by cancer cells and increasing apoptosis compared to non-targeted systems. Additionally, the microarchitecture of nanocarriers can interfere with therapeutic mechanisms. Wang et al. developed capsaicin-loaded core-shell multilayered microspheres to study their impact on digestive processes and colitis alleviation.[50] These microspheres facilitate the release of encapsulated capsaicin nanoparticles in the

www.advancedsciencenews.com www.advmattechnol.de Table 1. Typical capsaicin-based nanomaterials for TRPV1 activation. Materials Nanocarrier Load properties Size [nm] Surface modiﬁcation Applications Refs.

CAP@lipid Lipid nanoparticles EE: 35.7% to 49% 277.7 DSPE-PEG Reducing liver oxidative stress in mice [10a] CAP@lipid Lipid nanoparticles LE: 32.07 ± 0.8% EE: 86.13 ± 4.1% 108.5 Folic acid Treatment of ovarian cancer in mice

[10b] CyLiPns Nanoparticles with PLGA core and lipid shell LE: NA EE: 91.26 ± 4.63% 163 ± 9 DSPE-PEG Inhibiting skin inﬂammation in mice [49c] CAP NPs in MPs Nano-in-micro particles LE: 1.02 ± 0.16% EE: 88.66 ± 3.08%

Nano: ≈240.2 nm Micro: ≈212.84 μm NA Colitis amelioration in mice [50] SPN-C Semiconducting polymer nanoparticles LE: NA EE: 95.7% ≈33−40 DSPE-PEG In vivo cancer therapy [53] CSPN Semiconducting polymer nanoparticles

NA ≈95−115 PEG Treatment of U373 tumor-bearing mice [54] CAP@MSN Mesoporous silica nanoparticles LE: NA EE: 64.9% to 85.5% 50, 100, 400 NA Antioxidant meat preservation [56] CaCO3 @CAP-PEG CaCO3 nanoparticles

LE: 3.68 ± 0.35% 105 DSPE-PEG Treatment of liver cancer in mice [58] CAP@HSA HSA nanoparticles LE: 2.3% EE: 94% 153.5 ± 5.3 NA Treatment HOS tumor-bearing mice [59] CAP-BODIPY Self-assembled CAP-BODIPY nanoparticles

LE: NA EE: 100% ≈37 NA Treatment of prostate cancer in mice [60] EE: entrapment eﬃciency; LE: load eﬃciency; NA: not available.

intestine, fostering mucus-associated bacteria proliferation and eﬃciently triggering the TRPV1-mucus-microbiota cycle. Moreover, lipid nanoparticles enable the concurrent delivery of nucleic acids and drugs, achieving synergistic drug and gene therapy eﬀects. For example, Desai et al, developed a new biodegradable lipid-polymer hybrid nanoparticle system comprising cationic amphiphiles with cyclic pyrrolidinium head groups and poly (D, L-lactic-co-glycolic acid) (PLGA).[49c] This hybrid nanoparticle, consisting of a negatively charged hydrophobic PLGA core and a positively charged cationic lipid shell, can co-load hydrophobic capsaicin and anti-TNF𝛼 siRNA through self-assembly in aqueous solutions. Semiconducting polymer nanoparticles blend the beneﬁts of biocompatibility, photostability, and strong absorption coeﬃcients.[51] Tailored molecular design imparts versatile lightresponsive properties, ideal for diverse bio-applications.[52] Researchers recently developed an ion-channel targeted nanomedicine (SPN-C), which comprises semiconducting polymer nanoparticles as the photothermally responsive nanocarrier, and capsaicin as the TRPV1 agonist, DSPE−PEG2000 and DPPC as the lipid coating.[53] Under 808-nm laser irradiation, SPN-C release a high local concentration of capsaicin at the tumor site to activate TRPV1 channels, achieving speciﬁc cancer cell therapy at a low systemic administration dosage. However, in such nanomedicine, capsaicin is loaded via hydrophobic interaction, potentially causing burst release during circulation and undesired TRPV1 activation in normal organs. To improve the reliability of the delivery system, capsaicin can be integrated into nanocarriers through chemical reactions and released only under speciﬁc stimuli. For instance, Fan et al. developed a phototheranostic nanomedicine (CSPN) by conjugating capsaicin with semiconducting polymer nanoparticles via a singlet oxygenresponsive thioketal linker.[54] Under 635-nm laser irradiation, Adv. Mater. Technol. 2024, 2401355

CSPN generates 1 O2 to cleave the thioketal linker, releasing free capsaicin after hydrolysis, enabling ﬂuorescence imaging-guided light-controlled Ca2+ -overload cancer therapy. In addition to organic nanocarriers, inorganic nanomaterials oﬀer promising prospects for drug delivery due to their aﬀordability, inherent stability, and tunable physicochemical properties. Mesoporous silica nanoparticles, in particular, stand out for drug delivery for their highly ordered porous structure and adjustable pore size.[55] Si et al. demonstrated the exceptional loading capacity of mesoporous silica nanoparticles for capsaicin, reaching 854.77 mg g−1 .[56] Furthermore, smaller-sized nanoparticles exhibit a heightened sustained release rate of capsaicin, consequently enhancing oxidation resistance in meat preservation. Calcium carbonate is a promising targeted delivery system due to its good biocompatibility and degradability under acidic conditions.[57] Recently, Xu et al. developed capsaicinloaded CaCO3 nanoparticles with good dispersibility and stability in aqueous solution, enabling pH-responsive capsaicin release for TRPV1-activated tumor-speciﬁc therapy.[58] The excellent pHresponsive degradability of CaCO3 prevents capsaicin leakage in the bloodstream, ensuring speciﬁc release only in the acidic tumor microenvironment.

3.2. Photothermal Nanomaterials Optical stimuli, particularly utilizing NIR light, are notable for their deep tissue penetration, low phototoxicity, and non-invasive manipulation of speciﬁc cells or biological tissues. Photothermal nanomaterials can respond to speciﬁc wavelengths of light, inducing localized thermal eﬀects useful for applications such as neuromodulation, cancer treatment, and photoacoustic imaging. Unlike visible light, NIR light penetrates biological tissues deeply

www.advancedsciencenews.com www.advmattechnol.de Table 2. Photothermal nanomaterials for TRPV1 activation. Materials Trigger source Power density Size [nm] Temporal response Surface modiﬁcation Applications

Refs. 532-nm laser (pulse) 0.174 Wcm−2 ≈20 ≈ms (cell) Streptavidin In vitro activating neurons [61b] Gold nanorods 785-nm laser 0.08 Wcm−2 NA NA High-density lipoprotein In vitro activating single neuronal cells

[61c] Gold nanorods 915 or 980-nm laser NA W: ≈20; L: ≈70-120 ≈ms (cell) Anti-TRPV1 Light–guided mouse behavior [61e] AuNPs Carbon nanohorns 800-nm laser 1.04 Wcm−2 NA NA NA In vitro activating cells [64a]

Graphdiyne 800-nm laser 0.01 Wcm−2 D: ≈100; H: ≈5 ≈ms (cell) Anti-TRPV1 In vivo neuromodulation [64b] CuS 980-nm laser 5.0 Wcm−2 13 ± 1.2 NA Anti-TRPV1 In vivo attenuating atherosclerosis in mice [63a]

CuS @CaCO3 1064-nm laser 1.2 Wcm−2 ≈100 NA DSPE-PEG Treatment of HepG2 tumor-bearing mice [63b] Cu2-x Se 1064-nm laser 1.0 Wcm−2 4.3 ± 1.2 NA Anti-TRPV1 Treatment of Parkinson’s disease in mice [71] PtNP-shell

1064-nm laser 0.45-0.8 Wcm−2 200.1 12 ± 3 s (dog) 35 ± 5 s (cell) mPEG-SH5000 Preventing ventricular arrhythmias in dogs [62] ICG-micelles 808-nm laser ≈1.0 Wcm−2 ≈35 NA Anti-TRPV1 In vitro activating neuronal cells

[65] SPNbc 808-nm laser 1.04 Wcm−2 ≈25-37 ≈0.1 s (cell) Anti-TRPV1 In vitro activating neurons [66] MINDS 1064-nm laser 0.8-1.0 Wcm−2 ≈40 5.0 ± 1.5 s (mouse) 0.9 ± 0.2 s (cell) PLGA-PEG Deep-brain stimulation in mice

[11b]

Note: MINDS is the abbreviation of macromolecular infrared nanotransducers for deep-brain stimulation, which is composed of a poly(benzobisthiadiazole-alt-vinylene) core and a PLGA-PEG shell.

with minimal attenuation and photodamage. When directed to speciﬁc cells or tissues, these nanoparticles increase local temperatures, activating TRPV1 channels on cell membrane. Over the past decade, various photothermal nanomaterials, such as platinum and gold nanoparticles,[11a,61,62] copper sulﬁde (CuS) nanoparticles,[63] carbon-based nanomaterials,[64] ICG,[65] semiconductor polymer dots,[11b,52a,66] and polydopamine (PDA),[61g] have been employed for TRPV1 activation (Table 2). Gold nanoparticles, in shapes like nanospheres and nanorods, use their unique optical properties and localized surface plasmons to achieve photoinduced functions.[67] Illumination at their resonant frequency enables eﬃcient light absorption and converts the absorbed energy into heat.[68] As the length-to-diameter ratio increases, the longitudinal dipole plasmon wavelength of gold nanoparticles shifts from visible to infrared,[69] allowing for the activation of temperature-sensitive ion channels across diﬀerent scenarios. For instance, spherical gold nanoparticles with strong absorbance in the visible range were precisely targeted to the cell membranes of dorsal root ganglion neurons via streptavidin surface modiﬁcation.[61b] Optical stimulation effectively elicited action potentials with remarkable robustness, even at low concentrations of gold nanoparticles, when exposed to pulsed laser irradiation at 532 nm. Additionally, Nakatsuji and colleagues utilized the local heating of gold nanorods under 780 nm excitation to activate TRPV1 channels in intact cell plasma membranes.[61c] CuS nanoparticles exhibit NIR absorption due to the d-d transition of Cu2+ ions, unlike gold nanostructures and carbon nanotubes which rely on surface plasmon resonance for optical ab- Adv. Mater. Technol. 2024, 2401355

sorption. This unique property gives CuS nanoparticles excellent photothermal conversion eﬃciency and broadband absorption that extends beyond 1000 nm. Consequently, they oﬀer distinct advantages for activating thermal-sensitive ion channels, particularly in relevant in vivo biological applications.[63] For instance, Gao et al. developed a photothermal switch for TRPV1 signaling in vascular smooth muscle using CuS nanoparticles and a speciﬁc monoclonal antibody interaction.[63a] Upon 1064-nm laser irradiation, a local temperature rise triggers TRPV1 channel opening within seconds, leading to a substantial Ca2+ inﬂux. Small CuS nanoparticles can also be encapsulated in biocompatible CaCO3 nanocarriers to create intracellular Ca2+ cascade reactors for tumor therapy by photothermal activation of TRPV1 channels.[63b] In the acidic tumor microenvironment, CaCO3 nanocarriers decompose and release suﬃcient Ca2+ , which enters tumor cells through photothermally activated TRPV1 channels and disrupts mitochondrial Ca2+ homeostasis and function, ultimately leading to apoptosis. Additionally, copper selenide (Cu2-x Se) nanocrystals, with strong absorption beyond 1000 nm and excellent photothermal conversion eﬃciency, show promising potential for tumor photothermal therapy and photoacoustic imaging.[70] Organic photothermal agents oﬀer enhanced biodegradability and biocompatibility compared to inorganic counterparts, thereby expanding their clinical utility. For example, ICG, an FDA-approved small molecule dye, exhibits remarkable photothermal eﬀects and ﬂuorescence emission when exposed to NIR light, making it a powerful platform for biomedical therapeutic and diagnostic applications. Recently, Chen et al.

www.advancedsciencenews.com www.advmattechnol.de Table 3. Magnetothermal nanomaterials for TRPV1 activation. Materials Trigger source Magnetic ﬁelds Size [nm] Fe3 O4 Radiofrequency ﬁeld 465 kHz, 5 mT Ferritin

Temporal response Surface modiﬁcation Applications Refs. ≈20 NA Anti-His NA NA Regulate plasma glucose in mice [13a] NA Fe3 O4 Alternating magnetic ﬁeld 15 kA m−1 500 kHz ≈22 5 s (cell) PAA-PEG Deep brain stimulation in mice

[74a] Fe3 O4 Alternating magnetic ﬁeld 30 kA m−1 160 kHz ≈20 ≈10−15 s (cell) PMAO-PEG Alleviate parkinsonian-like symptoms in mice [74b] Fe3 O4 Alternating magnetic ﬁeld 40 kA m−1 165.7 ± 0.4 kHz ≈21 ± 1

>10 s (cell) PMAO-PEG In vitro nerve growth [74c] Fe3 O4 Alternating magnetic ﬁeld 15 kA m−1 515 kHz ≈22 >10 s (cell) 40 s (mouse) PMAO-PEG Wirelessly control adrenal hormone secretion in rats [74d] Radiofrequency ﬁeld

40 MHz, 8.4 G ≈6 6 s (C.elegans) 15 s (cell) Streptavidin Remote neurostimulation in C. elegans [75a] Co0.24 Fe2.76 O4 Alternating magnetic ﬁeld 70 kA m−1 50 kHz; 18.6 ± 1.1 >10 s (cell) PMAO-PEG In vitro activating HEK cells

[75b] CoFe2 O4 @MnFe2 O4 Alternating magnetic ﬁeld 22.4 kA m−1 412.5 kHz Core: 8.0 ± 1.0 Shell: 2.25 22.8 ± 2.6s (mouse) 2.18 ± 0.17 s (cell) PMA Deep brain stimulation in mice [78] Radiofrequency ﬁeld

175 MHz, 1.5A NA NA NA Mimicking congenital heart disease phenotypes [79b] MnFe2 O4 Ferritin

Note: PAA, PMA, and PMAO are the abbreviations of poly(acrylic acid), poly(maleic anhydride-alt-1-octadecene), and poly(isobutylene-alt-maleic-anhydride), respectively.

developed biodegradable ICG micelles using an amphiphilic block copolymer, demonstrating notable stability, biocompatibility, and photothermal eﬀects.[65] These micelles were engineered to target speciﬁc nerve cell membranes via TRPV1 antibody recognition and enable remote activation of TRPV1 channels upon 808 nm irradiation. Despite these advances, ICGbased nanomaterials suﬀer from relatively low photothermal conversion eﬃciency and a narrow absorption spectrum (within 1000 nm), which limit their potential in certain applications. To address this problem, a series of organic semiconductor polymer nanoparticles with high photothermal conversion eﬃciency and tunable NIR absorption wavelength have been designed and synthesized for molecular imaging, noninvasive bioactivation, and advanced therapy.[11b,52a,66] Wu et al. developed a macromolecular transducer with a semiconducting polymer core and an amphiphilic polymer shell, with has a size of ≈40 nm and a photothermal conversion eﬃciency of 71% at 1064 nm.[11b] These properties enable the remote activation of TRPV1expressing neurons in living mice with minimal thermal damage under 1064-nm irradiation at an incident power density of 10 mW mm−2 . 3.3. Magnetothermal Nanomaterials Magnetic ﬁelds are useful for remote stimulation due to their minimal interaction with biological molecules and deep penetration into the body. Magnetic nanomaterials, when exposed to alternating magnetic ﬁelds, dissipate heat through hysteresis, making them eﬀective transducers for external stimuli. The synthe- Adv. Mater. Technol. 2024, 2401355

sis of magnetic nanomaterials is well established, allowing precise control over their size, shape, composition, and structure for biomedical applications such as magnetic resonance imaging and magnetothermal therapy.[72] Fe3 O4 nanoparticles have attracted considerable attention, particularly since FDA approved products already exist,[73] indicating their potential for magnetogenetics (Table 3). When exposed to alternating magnetic ﬁelds, Fe3 O4 nanoparticles generate heat, activating TRPV1 channels and triggering widespread and reversible ﬁring of neurons.[13a,74] These nanoparticles, which are ≈20 nm in size, can be surface modiﬁed to suit various biological applications. Doping with transition metals such as Mn and Co enhances their magnetothermal properties, further optimizing TRPV1 activation.[75] For example, substitution of Fe3 O4 with Co disrupts d-orbital degeneracy, leading to stronger spinorbit coupling, increased magnetic anisotropy, and extended hysteresis loops.[75b] The aqueous dispersion of ultrasmall MnFe2 O4 nanoparticles (6 nm) can be rapidly heated under an FDAcompliant radiofrequency ﬁeld (40 MHz, 8.4 G).[75a] When conjugated with streptavidin, these nanoparticles localize to the speciﬁc cell membranes and activate TRPV1 channels by local heating, achieving magnetothermal neuromodulation in C. elegans. Moreover, the exchange interaction between hard and soft magnetic phases is a promising approach for magnetism tuning.[76] Core-shell engineering enables the coupling of hard and soft magnetic components in a single nanoparticle, maximizing speciﬁc power dissipation and enhancing magnetothermal conversion eﬃciency.[77] Munshi et al. synthesized core-shell magnetic nanoparticles (CoFe2 O4 @MnFe2 O4 ) with a core of 8.0 ± 1.0 nm

www.advancedsciencenews.com www.advmattechnol.de Table 4. Other functional nanomaterials for TRPV1 activation. Materials Activators Trigger source Size [nm] Temporal response Surface modiﬁcation Applications

Refs. Fe3 S4 NO Electrocatalysis 3 153 ± 2 s (cell) NA In vivo neurostimulation in mice [83] Zn-Mo NO Electrocatalysis NA >100 s (cell) NA In vitro activating HEK 293T cells [84] HCuS@PDATRPV1/BNN6 NO

808-nm laser ≈130 NA Anti-TRPV1 Treatment of U373 tumor-bearing mice [82a] NO/capsaicin GSH/proton ≈250 NA NA Treatment of pancreatic cancer/liver cancer in mice [82b] CAP-P-NO Ferritin H2 O2 Radiofrequency ﬁeld

NA >250 s (cell) NA In vitro activating N2a cells [86a] Ferritin H2 O2 Radiofrequency ﬁeld ≈5–6 NA GFP-tag In vitro activating HEK 293T cells [86b] Ferritin Mechanical stress Static magnetic ﬁeld NA NA

GFP-tag Remote regulation of glucose homeostasis in mice [13b] and a shell of 2.25 nm, which enabled robust and repetitive magnetothermal activation of motor behavior in awake, freely moving mice.[78] Endogenous ferritin can also convert alternating magnetic ﬁelds into heat, activating the TRPV1 channel.[13a,79] Ferritin, a heteromultimer of light and heavy chains, forms a paramagnetic iron oxide core of ≈5–12 nm,[80] generating heat in response to radiofrequency ﬁelds through Neel relaxation and Brownian motion. Two typical ferritin-based approaches to TRPV1 activation exist. One involves co-expressing chimeric anti-GFP-TRPV1 and GFP-tagged ferritin to link TRPV1 and ferritin via GFP,[13b,79a] while the other fuses TRPV1 with the ferritin-binding domain of kininogen-1, leading to endogenous ferritin iron redistribution to ion channels (FeRIC).[79b] In 2012, Stanley and colleagues showed that radiofrequency ﬁelds can heat intracellular ferritin, activating TRPV1 channels and stimulating proinsulin release by ≈67%, comparable to exogenous Fe3 O4 nanoparticles.[13a] They also developed a genetically encoded system using intracellularly synthesized iron oxide nanoparticles for remote regulation of gene expression.[39] This system controlled Ca2+ inﬂux and key protein expression in engineered stem cells but also demonstrated repeated regulation of plasma insulin and blood glucose levels in mice. Moreover, Hutson et al. found that exposing chicken embryos expressing TRPV1FeRIC in cardiac neural crest cells to radiofrequency ﬁelds can replicate congenital heart defect symptoms in human patients.[79b] However, the mechanism by which radiofrequency ﬁelds and ferritin inﬂuence the TRPV1 channel remains contentious.[81]

3.4. Other Nanomaterials Several NO nanomodulators have emerged to speciﬁcally modulate neurons by orchestrating synaptic plasticity and neurosecretion (Table 4). Typically, NO donors are integrated into nanocarriers to target disease sites and activate TRPV1 through the production of NO when exposed to speciﬁc stimuli.[82] A notable example is the work by Wang et al., who developed a nanoplatform that releases NO upon NIR stimulation. This platform uti- Adv. Mater. Technol. 2024, 2401355

lizes hollow CuS nanoparticles coated with polydopamine.[82a] When subjected to 808 nm irrradiation, the polydopamine layer generates active electrons, triggering the photochemical breakdown of the NO donor. This process results in the release of NO, which subsequently activates TRPV1 channels. Additionally, Anikeeva et al. have designed Fe3 S4 nanoclusters that catalyze NO generation from benign sodium under modest electric ﬁelds.[83] This approach enables localized NO production and activates NO-sensitive TRPV1 channels with tunable release kinetics through voltage modulation. Integration of these electrocatalytic nanoclusters into multimaterial ﬁbers extends their utility for NO-mediated neuronal interrogation in vivo by inducing controlled neuronal excitation in the ventral tegmental area region and excitatory projections in mice. Moreover, researchers have introduced a fully biodegradable galvanic cell system that facilitates in situ electrochemical NO generation to modulate cell behavior.[84] In the presence of a NaNO2 solution, the generated NO opens TRPV1 channels on HEK293T cell membranes, triggering the inﬂux of calcium ions. This in situ NO generation holds promise for further research into NO-associated biological processes and therapeutic methods. Intriguingly, ROS and oxidized lipids can also activate TRPV1 channels and increase their sensitivity to heat or capsaicin.[85] Recent studies have shown that radiofrequency ﬁelds can induce endogenous ferritin to produce ROS, which then activate TRPV1 channels (Table 4).[86] This process is facilitated by a ferritindependent increase in the labile iron pool in certain cells. The released iron participates in chemical reactions to generate H2 O2 and oxidized lipids, which activate the ferritin-tethered TRPV1 channel and enhance Ca2+ inﬂux. However, an excess of ROS can lead to oxidative stress, posing a threat to neurons and glial cells, possibly contributing to neurodegenerative diseases.[87] Therefore, nanomaterials that can scavenge ROS are promising candidates for the treatment of diseases such as ischemic stroke and Alzheimer’s disease.[88] Ferritin iron oxide nanoparticles can convert an external magnetic ﬁeld into mechanical force when neighboring particles align with the ﬁeld.[89] TRPV1 shares 40% amino acid identity

www.advancedsciencenews.com www.advmattechnol.de with the mechanosensitive, non-selective cation channel TRPV4, which is activated in response to membrane tension or direct mechanical force.[90] Stanley et al. hypothesized and tested whether an external magnetic ﬁeld could exert a mechanical force on ferritin to activate TRPV1 channels.[13b] In contrast to heating by a radiofrequency ﬁeld, a static magnetic ﬁeld was used to exert a mechanical force on ferritin-tethered TRPV1. Moving a standard stationary magnet over HEK cells activated ferritin-tethered TRPV1, conﬁrming the responsiveness of TRPV1 channels to mechanical forces.

4. Biomedical Applications 4.1. Neuromodulation TRPV1 is widely distributed in the mammalian peripheral nervous system, including dorsal root ganglion and trigeminal ganglion neurons, nerve terminals, and the cornea. It serves as an intrinsic thermosensitive ion channel for precise regulation of Ca2+ in neuronal cells. Activation of TRPV1 leads to elevated intracellular Ca2+ levels, triggering the release of inﬂammatory mediators and neurotransmitters from nerve terminals for signal transmission. Functional nanomaterials are often essential to generate localized heat in response to external stimuli such as magnetic ﬁeld and light. Nanomaterial-mediated neuromodulation, particularly within the deep brain, has become a power tool for understanding neural communication and holds promise for the diagnosis and treatment of neurological disorders such as Parkinson’s disease.[9] Magnetothermal neuromodulation was ﬁrst demonstrated in vitro and in C. elegans in 2010,[75a] and more recently applied in mice and rats.[74a,d,78] Initial studies used anaesthetized animals,[74a] but later studies evoked involuntary behaviors in freely moving mice.[78] Surface modiﬁcation of nanoparticles is essential for enhancing their in vivo biocompatibility and enabling targeted interaction with ion channels on cell membranes. Depending on the application, nanoparticles can be directly injected into speciﬁc brain regions or organs.[74d,78] For instance, Chen et al. used lentiviral delivery of TRPV1 to sensitize excitatory neurons in the ventral tegmental area of mice to heat, followed by localized injection of Fe3 O4 nanoparticles into the same region four weeks later.[74a] Exposure to alternating magnetic ﬁelds (15 kA m−1 , 500 kHz) induced neuronal excitation, as evidenced by the upregulation of the immediate early gene c-fos (Figure 4a). However, due to the slow heat generation, magnetothermal neuromodulation often require tens of seconds to elicit an increase in Ca2+ inﬂux,[75a,78,79c] which may surpass the temporal dynamics of neuronal ﬁring. In contrast, photothermal neuromodulation enables TRPV1 activation within milliseconds,[61b,66,91] allowing manipulation of the behaviors of freely moving animals without the spatial conﬁnement of a magnetic coil (Figure 4b). A recent study demonstrated that photothermal neuromodulation with TRPV1 activation induces NIR light sensitivity in remaining photoreceptor cell bodies of blind mice and in ex vivo human retinas.[61e] Researchers expressed TRPV1 channels in light-insensitive retinal cones in a mouse model of retinal degeneration, leading to enhanced activity in cones, ganglion cell layer neurons, and cortical

neurons upon NIR stimulation, ultimately enabling mice to exhibit learned light-driven behaviors (Figure 4c). TRPV1 is also an eﬀective target for treating neurodegenerative diseases.[92] Recent studies have highlighted the potential of magnetothermal and photothermal nanomaterial-mediated TRPV1 modulation in treating Parkinson’s disease.[71,74b] For instance, Yuan et al. have demonstrated that utilizing Cu2-x Se nanoparticles to activate TRPV1 channels in microglia signiﬁcantly enhances autophagy, leading to improved clearance of 𝛼-synuclein for Parkinson’s disease treatment.[71] Under 1064-nm irradiation, the localized heat activates TRPV1 channels, causing Ca2+ inﬂux, which triggers the ATG5 and Ca2+ /CaMKK2/AMPK/mTOR signaling pathway, promoting phagocytosis and 𝛼-synuclein degradation (Figure 4d). As a result, the athletic performance of Parkinson’s disease mice improved signiﬁcantly, with key markers such as tyrosine hydroxylase, ionized calcium binding adapter protein 1, glial ﬁbrillary acidic protein, and pSer129-𝛼-syn, returning to levels comparable to healthy mice.

4.2. Cancer The TRPV1 channel exhibits heightened expression in many aggressive tumors such as breast, lung, hepatocellular, colorectal, pancreatic, and glioblastoma in the brain.[93] Cytosolic free Ca2+ serves as a pivotal regulator in cancer, inﬂuencing essential downstream phenomena in cancer, spanning proliferation, diﬀerentiation, and gene transcription. Consequently, activation of TRPV1 induces Ca2+ inﬂux, potentially perturbating intracellular pathophysiological events and instigating cancer cell demise. Unlike most nanomedicines that non-speciﬁcally induce cell apoptosis from inner organelles, nanomaterialmediated TRPV1 modulation can speciﬁcally act on the TRPV1-overexpressed cell membranes to initiate cancer cell apoptosis. A typical role of these nanomaterials is to act as delivery carriers for agonists, controlling their release through external stimulation or in response to the tumor microenvironment to activate TRPV1 channels for cancer treatment.[10b,53,54,58,60,94] NIR light eﬃciently triggers the release of capsaicin from nanomaterials (Figure 5a), rapidly increasing capsaicin levels within the cellular microenvironment.[53] This capsaicin consistently activates TRPV1 channels, resulting in Ca2+ overload and mitochondrial membrane potential depolarization. Subsequently, cytochrome c is released, initiating caspase-3 activation and ultimately inducing apoptosis in glioma cells. Moreover, some nanomaterials can respond to NIR light by generating localized heat around cell membranes for cancer treatment.[63b] The elevated temperature activates the TRPV1 channel and induces Ca2+ inﬂux, leading to the disruption and dysfunction of mitochondrial Ca2+ homeostasis and subsequent glioma cell apoptosis (Figure 5b). It is noteworthy that this heat-activated TRPV1 mechanism for cancer treatment diﬀers from conventional photothermal therapy, which directly destroys tumor cells through localized thermal eﬀects.[95] Nanomaterial-mediated TRPV1 modulation can enhance tumor sensitivity to various therapeutics such as photodynamic therapy,[59] chemodynamic therapy,[82a] and radiotherapy.[59,82b]

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Figure 4. Nanomaterial-mediated TRPV1 modulation for neuromodulation. a) Magnetothermal eﬀect of Fe3 O4 nanoparticles. Wireless deep brain stimulation is achieved by exposing Fe3 O4 nanoparticles to alternating magnetic ﬁelds (left). Confocal images of a coronal slice show increased c-Fos expression in the ventral tegmental area after stimulation and sacriﬁce of the mice (right). Reproduced with permission from ref. [74a]. Copyright 2015 American Association for the Advancement of Science. b) NIR-II photothermal deep-brain stimulation in freely behaving mice. The conditioned place preference test was conducted within a Y-maze, and the post-test heatmaps display the travel time of the mice under diﬀerent experimental conditions. Reproduced with permission from ref. [11b]. Copyright 2022 Springer Nature. c) NIR photothermal stimulation of the mouse retina. Mice respond by licking before or after the appearance of water. The lick response heatmaps show the behavioral responses of mice under diﬀerent experimental conditions. Reproduced with permission from ref. [61e]. Copyright 2020 American Association for the Advancement of Science. d) Treatment of Parkinson’s disease via NIR-II photothermal stimulation. A schematic illustration shows that photothermal stimulation enhances microglial autophagy, promoting the phagocytosis and degradation of 𝛼-synuclein. Reproduced with permission from ref. [71]. Copyright 2022 Wiley.

An example of this is the dual-channel Ca2+ nanomodulator (CAP-P-NO) developed by Wang et al. This innovative system integrates capsaicin and a NO moiety into a self-assembling peptide, achieving tumor radiosensitization by inducing endogenous Ca2+ redistribution.[82b] The acidic and glutathione-rich tumor environment triggers the release of capsaicin and NO, which activate TRPV1 and ryanodine receptors, respectively. This activation leads to an inﬂux of extracellular Ca2+ and the release of Ca2+ from the endoplasmic reticulum. The resulting high levels of Ca2+ in tumor cells disrupt organelle function and induce widespread transcriptome changes, including the downregulation of radioresistance-associated genes, thereby enhancing the radiosensitization of both pancreatic and patient-derived hepatic tumors (Figure 5c). Immunotherapy shows potential in cancer treatment by not only activating immune cells to control the growth of the pri- Adv. Mater. Technol. 2024, 2401355

mary tumor, but also creating immunological memory cells to prevent metastasis and recurrence.[96] The TRPV1 channel can inﬂuence the expression of heat shock protein 70 (HSP70) and transforming growth factor 𝛽 (TGF𝛽) proteins,[97] suggesting a possible role in regulating self-defense behaviors in cancer cells during treatment. A recent study demonstrated that nanomaterial-mediated TRPV1 blockade selectively inhibits stressful HSP70 and TGF𝛽1 by eﬃciently modulating HSF1 to enhance thermal immunotherapy against highly malignant tumors (Figure 5d).[63c] Upon NIR irradiation, the ICG/TRPV1 antagonist-loaded polymeric nanoparticles exhibit signiﬁcant antitumor eﬃcacy across various primary, metastatic, and recurrent tumors. TRPV1 blockade inhibits HSF1 nuclear translocation and downregulates TGF𝛽1, leading to the degradation of the extracellular matrix. This improves the inﬁltration of antiPD-L1 antibodies and immune cells into highly ﬁbrotic and

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Figure 5. Nanomaterial-mediated TRPV1 modulation for cancer treatment. a) Schematic of the proposed activation mechanism induced by photothermal TRPV1 nanoagonists. Reproduced with permission from ref. [53]. Copyright 2018 American Chemical Society. b) Schematic of the proposed apoptosis mechanism induced by the thermal eﬀect of CuS@CaCO3 -PEG nanoparticles under 1064-nm irradiation. Reproduced with permission from ref. [63b]. Copyright 2020 Cell Press. c) i) Schematic of nanomaterial-mediated dual-channel Ca2+ nanomodulator for tumor radiosensitization. ii) TUNEL and H&E staining of the tumor slices at 24 h post-radiation. Reproduced with permission from ref. [82b]. Copyright 2024 Wiley. d) Schematic of extracellular matrix remodeling to facilitate aPD-L1 inﬁltration, inducing a durable immune response via TRPV1 blockade-synergized thermotherapy. Reproduced with permission from ref. [63c]. Copyright 2023 Springer Nature.

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Figure 6. Nanomaterial-mediated TRPV1 modulation for cardiovascular diseases treatment. a) i) NIR photothermal activation of TRPV1 signaling to attenuate atherosclerosis using CuS-TRPV1 nanoparticles. ii) TEM images of CuS-TRPV1 nanoparticles targeting vascular smooth muscle cells. iii) attenuation of atherosclerotic lesions in ApoE− /− mice on a high-fat diet. Reproduced with permission from ref. [63a]. Copyright 2018 Springer Nature. b) i) Schematic of remote and precise control of urokinase plasminogen activator production for thrombolysis therapy using photothermal nanoparticles (PMSF−dylight -DBCO). These photothermal nanoparticles were bound to the surface of HEK293T cells and encapsulated into injectable hydrogels. The engineered cell-based hydrogel was implanted into mice with tail thrombus, and thrombolysis therapy was performed upon NIR irradiation. ii) Histological analysis of thrombus after indicated treatments. Reproduced with permission from ref. [101b]. Copyright 2019 Wiley. c) i) Schematic of photothermal nanomaterial (PtNP shell)-mediated multimodal autonomic modulation for the treatment of myocardial ischemia-reperfusion injury and myocardial ischemia-induced ventricular arrhythmias. ii) Location of the nodose ganglion in the canine parasympathetic nervous system. iii) Typical thermal imaging diagram of photothermally modulated activation of nodose ganglion under 1064 nm laser irradiation. Reproduced with permission from ref. [62]. Copyright 2024 Springer Nature.

www.advancedsciencenews.com www.advmattechnol.de immunosuppressive tumors, resulting in synergistic thermoimmunotherapy.

4.3. Cardiovascular Diseases TRPV1 is also widely distributed in the cardiovascular system, including cardiac muscle, cardiomyocytes, vascular endothelial cells, and smooth muscle cells.[98] Emerging evidence highlights TRPV1’s crucial role in cardiovascular health, including its regulation of lipid metabolism and energy balance, reduction of foam cell formation, induction of autophagy, mitigation of vascular endothelial damage, and inhibition of inﬂammation.[98a] The modulation of TRPV1 function by vasoactive mediators and its impact on sympathetic nerves contribute to control of blood vessel contraction and relaxation, thereby inﬂuencing hypertension development.[99] Moreover, activation of TRPV1 channels demonstrates a protective eﬀect against atherosclerosis in rodent models.[100] Given the extensive involvement in cardiovascular diseases, this section mainly focuses on the therapeutic potential of nanomaterial-mediated TRPV1 modulation against atherosclerosis and thrombus formation.[63a,101] This can be achieved either through the inherent regulatory function of TRPV1 in atherosclerosis or through the production of biomolecules for thrombolysis. For instance, Gao et al. have developed CuS nanoparticles conjugated with TRPV1 antibodies that enable speciﬁc targeting of vascular smooth muscle cells.[63a] Upon irradiation with a 1064-nm laser, TRPV1 channels are opened by local heating, inducing a Ca2+ inﬂux. Subsequent activation of Ca2+ -AMPK signaling leads to increased cholesterol eﬄux, enhanced autophagy, and reduced foam cell formation, ultimately mitigating atherosclerosis in high-fat diet-fed mice (Figure 6a). Zhang et al. achieved therapeutic eﬀects on thrombolysis by remotely controlling expression of urokinase plasminogen activator through the integration of metabolic glycan engineering and nanomaterial-mediated TRPV1 activation (Figure 6b).[101b] Photothermal nanotransducers covert NIR light into heat to open TRPV1 channels and trigger the synthetic signaling pathway to secret urokinase plasminogen activator on demand for thrombolytic therapy. Combining anti-inﬂammatory and lipidregulating drug like atorvastatin with nanomaterial-mediated TRPV1 modulation can further improve the therapeutic eﬀect.[101c] In addition, myocardial ischemia often leads to acute ventricular arrhythmias, complicating the prompt and eﬃcacious treatment of acute myocardial infarction.[102] Recent research has shown that photothermal nanomaterial-mediated modulation of the autonomic nervous system has potential in preventing myocardial ischemia and myocardial ischemia-reperfusion injury that follows intervention (Figure 6c).[62] When exposed to 1064 nm laser irradiation, photothermal nanotransducers activate temperature-sensitive TRPV1 and TREK1 channels, respectively, which result in parasympathetic activation and sympathetic inhibition, respectively. In a male canine model, this approach of photothermal autonomic neuromodulation has been shown to eﬀectively stabilize cardiac electrophysiology and reduce ventricular arrhythmias during both myocardial ischemiareperfusion injury and myocardial ischemia.

4.4. Metabolic Diseases Dysregulation of TRPV1 is linked to the development of both type 1 and type 2 diabetes.[103] Lee et al. performed metabolic studies on TRPV1 knockout and wild-type mice fed a high-fat diet (HFD) to assess insulin and leptin levels.[104] They found that TRPV1 deﬁciency exacerbated obesity and insulin resistance associated with HFD and aging, suggesting that TRPV1 has a major beneﬁt in regulating glucose metabolism and obesity. Moreover, feeding capsaicin to obese mice reduced fasting blood glucose levels, fat accumulation, insulin and leptin levels, enhanced fatty acid oxidation, and signiﬁcantly reduced inﬂammation and metabolic disorders.[105] Recently, nanomaterial-mediated TRPV1 modulation has shown potential in treating metabolic diseases. Jeﬀrey and colleagues have explored magnetothermal activation of TRPV1 using exogenous ferromagnetic nanoparticles or endogenous ferritin nanoparticles.[13,79a] When exposed to lowfrequency radio waves, the Ca2+ inﬂux stimulates the expression of bioengineered insulin genes driven by Ca2+ -sensitive promoters, eﬀectively controlling blood glucose levels (Figure 7a). Initially, they used iron oxide nanoparticles conjugated with antiHis antibodies to speciﬁcally bind the TRPV1 channel with an extracellular His × 6 epitope tag. However, due to the internalization of nanoparticles, repeated injections are required to achieve long-term blood glucose regulation.[13a] To solve this problem, they used genetically encoded endogenous ferritin nanoparticles to bind TRPV1 channels.[13b] They used three strategies: direct co-expression of TRPV1 and ferritin, co-expression of TRPV1 and ferritin fused to a cell membrane localization signal, and co-expression of TRPV1 with an anti-GFP antibody modiﬁed at the N terminus and a GFP-ferritin fusion protein. Moreover, they constructed a TRPV1 mutant based on the same anti-GFP– TRPV1 WT or mutant/GFP–ferritin system, which induced Cl− inﬂux upon activation to remotely activate or inhibit hypothalamic glucose-sensitive neurons, thereby increasing or decreasing blood glucose levels for bidirectional regulation (Figure 7b).[79a] Dual activation of calcium channels TRPV1 and TRPA1 can precisely regulate blood glucose homeostasis by promoting the secretion of glucagon-like peptide (GLP-1). For instance, Li et al. developed a biomimetic NIR nanoplatform by coating endocrine cell membranes of the small intestine onto the surface of conjugated oligomer nanoparticles.[106] Upon 808-nm laser irradiation, these biomimetic nanoparticles eﬀectively generate heat and ROS, thereby activating heat-sensitive TRPV1 and ROSsensitive TRPA1 channels in small intestinal endocrine cells, promoting Ca2+ inﬂux, stimulating GLP-1 secretion, and ultimately regulating blood glucose in mice (Figure 7c). Intestinal stimulation can be transmitted through the gutbrain axis, playing a crucial role in regulating metabolic homeostasis. For instance, Mac et al. developed a self-powered particulate stimulator system designed for the noninvasive treatment of obesity-associated metabolic disorders.[107] The innovative system consists of a TRPV1 agonist and piezoelectric BaTiO3 particles. Once oral administered, these particles target capsaicinsensitive nerve endings and produce mild electrical signals in response to gastric movement. This stimulation of vagal aﬀerent ﬁbers leads to reduced food intake, an increased metabolic rate, and ultimately improvements in dietary obesity in mice (Figure 7d).

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Figure 7. Nanomaterial-mediated TRPV1 modulation for blood glucose regulation. a) i) Schematic of antibody-coated ferrous oxide nanoparticle inducing cell activation and gene expression to regulate blood glucose. Exposure to a radiofrequency ﬁeld induces local nanoparticle heating, leading to opening of TRPV1 channels. ii) Eﬀects of radiofrequency ﬁeld treatment on nanoparticle-treated mice with tumors expressing TRPV1His and calciumdependent human insulin. iii) Insulin gene expression is signiﬁcantly increased in tumors expressing TRPV1His and calcium-dependent human insulin treated with nanoparticles and radiofrequency magnetic ﬁeld, but not in tumors expressing calcium-dependent human insulin alone without TRPV1His . Reproduced with permission from ref. [13a]. Copyright 2012 American Association for the Advancement of Science. b) Schematic of the system used for non-invasive, temporal activation or inhibition of neuronal activity to control glucose homeostasis and feeding in mice. Reproduced with permission from ref. [79a]. Copyright 2016 Springer Nature. c) Schematic of light-responsive nanoparticles for dual activation of TRPV1 and TRPA1 channels to regulate blood glucose homeostasis. Reproduced with permission from ref. [106]. Copyright 2023 American Chemical Society. d) Schematic of an oral self-powered stimulator system for targeted electrical stimulation of the gut-brain axis to treat obesity and metabolic disorders. Reproduced with permission from ref. [107]. Copyright 2024 Wiley.

www.advancedsciencenews.com www.advmattechnol.de 5. Challenges and Outlook the stability of the bio-interface is essential for maintaining consistent performance within the complex biological environment. A critical prerequisite for these advances is ensuring the biosafety of nanomaterials. While some materials such as indocyanine green (ICG) and Fe3 O4 nanoparticles have already received FDA approval, further optimization is needed to improve their eﬃcacy in TRPV1 modulation. Speciﬁcally, adjusting their properties could enhance their ability to interact with target cells while minimizing oﬀ-target eﬀects. Nanomaterials smaller than 5 nm are often preferred in clinical applications due to their lower risk of long-term accumulation in the body.[114] However, they may have limited loading capacity for therapeutic drugs and reduced passive targeting eﬃciency to speciﬁc tumors. Therefore, selecting and designing nanomaterials requires a careful balance between maximizing therapeutic eﬀects and minimizing side effects. Comprehensive evaluations of safety, eﬃcacy, and biotoxicity in both acute and chronic applications are essential to bring these innovations from the laboratory to the bedside. The principles underpinning nanomaterial-mediated TRPV1 modulation extend beyond TRPV1 to other ion channels, oﬀering a versatile platform for the targeted treatment of various conditions. By exploiting the unique activation mechanism of diﬀerent ion channels, we can design tailored nanomaterials for speciﬁc biomedical applications. In summary, the potential of nanomaterial-mediated TRPV1 modulation is enormous and transformative. As we reﬁne these technologies and address existing challenges, we are on the cusp of a new era of precision medicine, where targeted, non-invasive modulation of ion channels can revolutionize the treatment and management of a wide range of diseases.

Nanomaterial-mediated TRPV1 modulation is at the frontier of biomedical innovation, oﬀering unprecedented precision in activating and inhibiting TRPV1 channels within deep tissues. This approach promises non-invasive and targeted therapeutic interventions in various diseases. Despite considerable progress, the development of functional nanomaterials for TRPV1 modulation remains in its infancy, presenting a landscape full of challenges and opportunities. Current research highlights the potential of nanocarriers to improve the bioavailability and half-life of TRPV1 agonists such as capsaicin. However, conventional nanocarriers often suﬀer from limited loading and encapsulation eﬃciency, necessitating high doses (Table 1). The advent of self-assembling therapeutic compounds into nanomedicines could revolutionize this ﬁeld by achieving 100% encapsulation eﬃciency and minimizing side effects. Capsaicin-BODIPY conjugates, for example, have demonstrated the ability to self-assemble into nanoaggregates, signiﬁcantly reducing the eﬀective dose required for therapeutic eﬀects in prostate cancer.[64a] Beyond traditional TRPV1 activators like capsaicin and heat, other stimuli such as low pH and various endogenous lipids have also shown eﬃcacy in TRPV1 activation.[108] This broadens the horizon for designing multifunctional nanomaterials. For example, pH-responsive nanomodulators could precisely regulate the local pH around speciﬁc cell membranes to eﬀectively trigger TRPV1 channels.[109] Moreover, designing nanomaterials that integrate multiple activation mechanisms such as pH sensitivity, heat response, and capsaicin release could provide new approaches for investigating TRPV1-related physiological and pathological processes. While photothermal and magnetothermal nanomaterials hold signiﬁcant potential for controlled TRPV1 activation, they come with certain challenges. One major issue is the risk of overheating, which may cause damage to surrounding tissues, particularly sensitive areas like the nervous system.[110] These materials may also inadvertently activate other receptors or proteins, leading to oﬀ-target eﬀects.[111] Another concern is the possible overexpression of heat shock proteins, which can interfere with normal cellular functions and stress responses.[112] To avoid these issues, it is crucial to enhance the conversion eﬃciency of these nanomaterials and implement real-time monitoring of temperature distribution during their application, ensuring both safety and precision in their use. In addition, the penetration depth of light and the practicality of magnetic ﬁeld application in patients with metal implants pose signiﬁcant challenges. Alternatively, ultrasound and X-rays, which oﬀer deep tissue penetration and operational ﬂexibility, are widely used in clinical settings. Recent developments in ultrasound- and X-ray-responsive nanomaterials for bioimaging, biosensing, and cancer treatment suggest a new dimension of TRPV1 modulation.[113] Designing nanomaterials responsive to these stimuli could enable the generation of heat and mechanical force or the release of TRPV1 agonists and antagonists, opening new avenues for non-invasive therapies. For the clinical translation of these technologies, several key challenges must be addressed. Achieving cell-speciﬁc control and ensuring the precise, localized delivery of external stimuli are critical for eﬀective treatment outcomes. Moreover, enhancing

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# 纳米材料介导的TRPV1离子通道调控及其生物医学应用

## 综述

瞬时受体电位香草酸通道（TRPV1-6）是多模态跨膜蛋白，主要定位于多种细胞类型和组织的质膜上。这些通道对于感觉感知、疼痛感知、体温调节和细胞稳态等生理过程至关重要。[1] 其中，TRPV1由David Julius及其同事于1997年首次从大鼠背根神经节中克隆，引起了广泛关注。[2] 作为一种非选择性阳离子通道，TRPV1促进Ca²⁺、Na⁺和Mg²⁺的内流，可被多种物理和化学刺激激活，包括激动剂、[2,3] 有害热刺激（≥42°C）、[4] 质子、[5] 以及活性氧和活性氮物种。[6] 尽管TRPV1主要分布于与疼痛感知相关的初级感觉神经元中，[5,7] 但它也在膀胱、胰腺和睾丸等非神经元细胞中表达，提示其具有更广泛的生理学意义。[8]

TRPV1的调控较为复杂，因其组织位置及特定生理或病理环境而异。多种激动剂引起的敏化涉及复杂的调控机制，影响其在不同场景中的功能。鉴于TRPV1参与众多生理和病理过程，它已成为多种疾病（包括癌症、神经退行性疾病、心血管疾病和疼痛管理）的有前景的治疗靶点。

在过去十年中，功能纳米材料已成为以高时空分辨率和特异性精确调控TRPV1信号通路的有效工具，[9] 尤其在深部组织中。这些纳米材料可作为换能器，响应pH、光、电场和磁场等内部或外部刺激，精确释放或产生TRPV1激活所需的激活剂。这种方法为与TRPV1功能障碍相关的疾病提供了非侵入性、靶向性的治疗干预手段。

纳米材料的选择和优化对于实现精确高效的TRPV1激活至关重要。例如，脂质纳米颗粒可在局部递送辣椒素以激活TRPV1，同时最小化毒性。[10] 金纳米棒等光热纳米材料可利用近红外（NIR）光快速激活TRPV1。[11] 然而，NIR光在组织中的穿透深度有限，限制了其临床应用。[12] 或者，Fe₃O₄纳米颗粒和铁蛋白等磁性纳米材料可在交变磁场作用下通过热量或磁力激活TRPV1，有效靶向深部组织。[13] 然而，磁热产生过程缓慢，通常需要数十至数千秒才能引发Ca²⁺内流，这超过了神经元放电的时间动力学范围。

在本综述中，我们旨在总结纳米材料介导的TRPV1调控策略及其生物医学应用（图1）。我们首先介绍负责门控TRPV1通道的各种激活剂及其各自机制。然后重点介绍纳米材料与TRPV1调控的整合，重点关注在不同场景中高效激活TRPV1所需的材料特性。我们探讨了纳米材料介导的TRPV1调控的生物医学应用，包括精确神经刺激和帕金森病等神经系统疾病的治疗、免疫治疗等癌症治疗、代谢性疾病治疗以及动脉粥样硬化等心血管疾病的干预。最后，我们讨论了该新兴领域面临的挑战和可能的解决方案。

## 2. TRPV1激活机制

TRPV1通道具有四聚体结构，每个亚基由几个结构域组成（图2a）：N端结构域（包括锚蛋白重复序列结构域）、跨膜结构域、TRP结构域和C端结构域。[14] 跨膜结构域包含电压门控样结构域（S1-S4）和孔道结构域（S5、S6）。值得注意的是，孔道结构域在细胞外侧附近具有"倒置帐篷"结构，构成选择性过滤器；在细胞内侧附近具有交错结构，形成下门。激活后，TRPV1的选择性过滤器和下门均可独特地扩张至更大尺寸，允许Ca²⁺和Na⁺等离子通过通道。在本节中，我们介绍门控TRPV1通道的不同激活剂，包括外源性和内源性激动剂、热和质子，以及它们的作用机制。为了提供清晰直观的理解，我们绘制了TRPV1通道主要激活信号和关键氨基酸位置的示意图（图2b）。

### 2.1 外源性和内源性激动剂

有多种外源性和内源性激动剂与TRPV1上的关键氨基酸结合，启动各种信号级联反应。外源性激动剂包括天然和合成化学物质，如辣椒素及其类似物、胡椒碱、[15] 丁香酚、[16] 姜辣素、[17] 树脂毒素、[2] 和双结毒素。[18]

辣椒素是辣椒中的辛辣成分，是首个被鉴定的TRPV1通道特异性激动剂。[2] TRPV1对辣椒素表现出高选择性（不激活TRPV2-6）和高敏感性（EC50约为亚微摩尔级）。[2,19] 被辣椒素激活后，伤害性神经元经历Ca²⁺和Na⁺的快速内流，导致细胞去极化、动作电位产生和辛辣感。[2] 研究已鉴定出辣椒素在TRPV1上的特异性作用位点，包括Y512、S513、T551、E571和S4-S5连接子。[19,20] 辣椒平是首个TRPV1拮抗剂，通过与辣椒素相同位点的竞争性结合来抑制通道开放。[21]

树脂毒素（RTX）等辣椒素类似物也可激活TRPV1，显著影响体温调节和神经源性炎症。[2] 这些类似物的效力水平比辣椒素高3-4个数量级。[22] 突变研究鉴定出Y511、S512、M547和T550残基对香草醛配体有响应。此外，具有结构类似序列的蜘蛛毒素，如双结毒素（DkTx），已被证明可与TRPV1相互作用。在激活状态下，两个二价DkTx分子参与此相互作用，[18,23] 敏感性的关键残基包括I599、F649、A657和F659。[17]

除外源性激动剂外，TRPV1的内源性配体也已被鉴定，如缓激肽、[3a] 三磷酸腺苷、[24] 神经生长因子、[3a] 花生四烯酸乙醇胺、[3b] 花生四烯酸代谢物、[3c] 和脂氧合酶产物。[3d] 这些内源性调节剂在炎症和伤害感受中起关键作用，但通常表现出低效力和高激活阈值。在病理条件下，内源性调节剂可协同激活TRPV1，突显其在生理反应中的重要性。例如，缓激肽可与G蛋白偶联受体（特别是B2受体）结合，通过信号级联激活蛋白激酶C。这种激活导致TRPV1磷酸化，使其对热、质子和辣椒素等其他刺激更敏感。[3a,25] 类似地，花生四烯酸乙醇胺与特异性残基（Y511、S512、Y554和Y555）相互作用，促进Ca²⁺内流。这种相互作用通过激活蛋白激酶A和C信号级联使TRPV1敏化。[26]

### 2.2 热激活

TRPV1可被高于42°C的热刺激激活，[4] 表现出高温度敏感性，Q10值约为25，而一般温度敏感性离子通道的Q10值范围为2至3。[2,27] 热刺激激活TRPV1通道的功效约为辣椒素的25%，产生的动作电位偏好Ca²⁺和Mg²⁺离子。[28] 改变或重组含TRPV1的人工系统膜组成的实验证实了其内在温度敏感性。[29] 激活动力学研究表明，温度主要调节TRPV1的开放速率。[4,29a,30] 温度感应结构被认为位于N端和C端、[31] 孔道结构域、[14a,32] 孔道塔、[33] 和孔道环。[34] 例如，TRPV1和TRPM8通道C端区域的交换改变了它们的敏感性，表明该区域在热激活中的重要性。[31b] TRPV1和PV2之间的结构域改变揭示了锚蛋白重复序列结构域N端区域在连接初始跨膜段以实现温度敏感性中的关键作用。[29b] 此外，TRP结构域的完整性对有效门控至关重要，E692、R701和T704残基在TRPV1活性中发挥重要作用。[27a] 尽管研究广泛，但TRPV1中启动温度反应的特定位点仍未被鉴定。

### 2.3 质子激活

与酸敏感离子通道（ASICs）类似，TRPV1可在正常生理温度下被低细胞外pH值（<6.0）激活。[28,35] 这种酸性还可使TRPV1对其他激动剂更敏感，通过降低激活阈值导致痛觉过敏。[2,36] 例如，在22°C时，质子激活的半最大有效pH值为5.4，质子激活诱导的电流强度约为饱和辣椒素激活产生的20%-30%。[28]

TRPV1通道的质子激活涉及特异性氨基酸。[28,37] E600与质子增强相关，E648是潜在的直接激活位点。[38] 在无配体结构中，E600与相邻亚基的R455形成盐桥。低pH暴露导致E600侧链旋转远离R455，破坏相互作用，并可能导致E648质子化，将孔环转变为开放构象。E648的突变可特异性消除质子诱导的激活，而不影响对辣椒素和热等其他刺激的响应。此外，T633、V538或F660结构域的单残基突变可在保留辣椒素和热激活的同时消除质子诱导的电流。[39]

### 2.4 氧化应激激活

氧化应激可激活或敏化TRPV1通道，导致痛觉过敏。活性氧（ROS），包括过氧化氢（H₂O₂）、超氧阴离子（O₂⁻）、羟基自由基（·OH）和单线态氧（¹O₂），在此过程中最为常见。[40] TRPV1的氧化还原状态对其活性调控至关重要。还原剂（如二硫苏糖醇）[41] 和氧化剂（如二酰胺、Cu:Phe、氯胺-T和H₂O₂）[42] 均可增强TRPV1活性。半胱氨酸的共价修饰，特别是亚基间二硫键，是TRPV1氧化敏化的基础。点突变研究鉴定出大鼠中的C621、鸡中的C772和C783是影响TRPV1活性的氧化应激关键位点。[42b] 人TRPV1具有独特的亚基间半胱氨酸二硫键，主要通过C258和C742建立，对通道稳定性有显著贡献。[43]

### 2.5 一氧化氮激活

一氧化氮（NO）是关键的气体信号分子，具有快速扩散能力，参与多种生理功能，包括神经传递、心血管稳态和免疫应答。[44] NO可通过半胱氨酸S-亚硝基化激活TRPV1通道，导致Ca²⁺内流并增加TRPV1对热和质子的敏感性。[6c] TRPV1中C616和C621的突变导致NO刺激的显著抑制。[6c] NO可激活培养的初级DRG神经元和表达TRPV1的CHO细胞，而广谱TRP通道拮抗剂钌红可完全阻断NO诱导的激活电流。[45] 此外，使用TRPV1激动剂和NO抑制剂对CA1锥体神经元电信号的研究证实了NO对海马中TRPV1介导的神经元信号传导的影响。[46]

## 3. 用于TRPV1调控的纳米材料

由于TRPV1的多种激活模式，可利用多种纳米材料调控TRPV1功能及相关生理过程。根据激活机制和触发模式，我们将激活TRPV1的纳米材料分为四类：基于辣椒素的纳米材料、光热纳米材料、磁热纳米材料以及与力、ROS和NO相关的其他纳米材料。这些分类涵盖了广泛的材料组成，包括有机小分子、聚合物、金属和无机纳米颗粒。在本节中，我们重点介绍纳米材料与TRPV1调控的整合，并讨论高效激活TRPV1所需的材料特性（图3）。

### 3.1 基于辣椒素的纳米材料

在过去二十年中，辣椒素作为最重要的TRPV1激动剂，在激活TRPV1通道方面表现出高敏感性，在癌症治疗和神经刺激等多种应用中前景广阔。然而，其固有的疏水性阻碍了体内的有效分布，导致高剂量时潜在的全身毒性。纳米医学的发展为提高治疗性辣椒素的生物活性、延长其生物利用度和减少副作用提供了新机遇（表1）。[47]

脂质纳米颗粒通常由可电离脂质、辅助脂质、胆固醇和聚乙二醇（PEG）-脂质组成，已成为有前景的药物递送平台。它们提供抗降解保护和增强的细胞摄取。[48] 这在近期COVID-19 mRNA疫苗成功后引起了广泛关注。脂质纳米颗粒最近成为辣椒素递送的理想系统。[10,49] 通过优化组分和制备方法，这些纳米颗粒可有效包封辣椒素，尺寸可调，并表现出良好的稳定性和生物相容性。[10a,49a,b] 表面修饰进一步增强了载辣椒素纳米颗粒对特定组织的靶向能力。例如，Lv等人开发了叶酸偶联的脂质纳米颗粒，将辣椒素主动靶向卵巢癌细胞，[10b] 增强了癌细胞摄取并增加了与非靶向系统相比的细胞凋亡。此外，纳米载体的微观结构可干扰治疗机制。Wang等人开发了载辣椒素核壳多层微球，研究其对消化过程和结肠炎缓解的影响。[50] 这些微球促进包封的辣椒素纳米颗粒在肠道中的释放，促进黏液相关细菌增殖，并有效触发TRPV1-黏液-微生物群循环。此外，脂质纳米颗粒可实现核酸和药物的共递送，实现协同药物和基因治疗效果。例如，Desai等人开发了一种新型可降解脂质-聚合物杂化纳米颗粒系统，包含具有环状吡咯烷鎓头基的两亲性阳离子物和聚（D,L-乳酸-共-乙醇酸）（PLGA）。[49c] 这种由带负电荷的疏水PLGA核心和带正电荷的阳离子脂质壳组成的杂化纳米颗粒可通过在水溶液中的自组装共载疏水性辣椒素和抗TNF-α siRNA。

半导体聚合物纳米颗粒兼具生物相容性、光稳定性和强吸收系数的优势。[51] 量身定制的分子设计赋予其多样的光响应特性，非常适合多种生物应用。[52] 研究人员最近开发了一种离子通道靶向纳米药物（SPN-C），其由作为光热响应纳米载体的半导体聚合物纳米颗粒、作为TRPV1激动剂的辣椒素、以及作为脂质涂层的DSPE-PEG2000和DPPC组成。[53] 在808 nm激光照射下，SPN-C在肿瘤部位释放高浓度的局部辣椒素以激活TRPV1通道，在低全身给药剂量下实现特异性癌细胞治疗。然而，在此类纳米药物中，辣椒素通过疏水相互作用负载，可能在循环期间引起爆发性释放和正常器官中不期望的TRPV1激活。为了提高递送系统的可靠性，辣椒素可通过化学反应整合到纳米载体中，并仅在特定刺激下释放。例如，Fan等人开发了一种光治疗纳米药物（CSPN），通过单线态氧响应的硫缩酮连接子将辣椒素与半导体聚合物纳米颗粒偶联。[54] 在635 nm激光照射下，CSPN产生¹O₂裂解硫缩酮连接子，水解后释放游离辣椒素，实现荧光成像引导的光控Ca²⁺过载癌症治疗。

除有机纳米载体外，无机纳米材料因其经济性、固有稳定性和可调的物理化学性质而在药物递送方面前景广阔。介孔二氧化硅纳米颗粒因其高度有序的孔结构和可调的孔径而在药物递送中脱颖而出。[55] Si等人证明了介孔二氧化硅纳米颗粒对辣椒素的优异载药量，达到854.77 mg g⁻¹。[56] 此外，较小尺寸的纳米颗粒表现出更高的辣椒素持续释放率，从而增强肉类保鲜中的抗氧化性。碳酸钙因其良好的生物相容性和酸性条件下的可降解性而成为一种有前景的靶向递送系统。[57] 最近，Xu等人开发了载辣椒素的CaCO₃纳米颗粒，在水溶液中具有良好的分散性和稳定性，实现pH响应性辣椒素释放用于TRPV1激活的肿瘤特异性治疗。[58] CaCO₃优异的pH响应性可降解性防止了辣椒素在血流中的泄漏，确保仅在酸性肿瘤微环境中特异性释放。

### 3.2 光热纳米材料

光刺激，特别是利用近红外光，因其深层组织穿透、低光毒性和对特定细胞或组织的非侵入性操控而备受关注。光热纳米材料可响应特定波长的光，诱导局部热效应，适用于神经调节、癌症治疗和光声成像等应用。与可见光不同，近红外光可深入穿透生物组织，衰减和光损伤最小。当靶向特定细胞或组织时，这些纳米颗粒升高局部温度，激活细胞膜上的TRPV1通道。

在过去十年中，多种光热纳米材料已被用于TRPV1激活（表2），包括铂和金纳米颗粒、[11a,61,62] 硫化铜（CuS）纳米颗粒、[63] 碳基纳米材料、[64] ICG、[65] 半导体聚合物点、[11b,52a,66] 和聚多巴胺（PDA）。[61g]

金纳米颗粒（如纳米球和纳米棒）利用其独特的光学特性和局域表面等离子体实现光诱导功能。[67] 在其共振频率下照射可实现高效光吸收并将吸收的能量转化为热量。[68] 随着长径比增加，金纳米颗粒的纵向偶极等离子体波长从可见光移至红外，[69] 允许在不同场景中激活温度敏感性离子通道。例如，在可见光范围内具有强吸收的球形金纳米颗粒通过链霉亲和素表面修饰精确靶向背根神经节神经元的细胞膜。[61b] 在532 nm脉冲激光照射下，即使金纳米颗粒浓度较低，光刺激也能有效诱发动作电位，表现出显著的稳健性。此外，Nakatsuji及其同事利用金纳米棒在780 nm激发下的局部加热来激活完整细胞质膜中的TRPV1通道。[61c]

CuS纳米颗粒由于Cu²⁺离子的d-d跃迁而表现出近红外吸收，不同于依赖表面等离子体共振进行光学吸收的金纳米结构和碳纳米管。这一独特性质赋予CuS纳米颗粒优异的光热转换效率和超过1000 nm的宽带吸收。因此，它们在激活热敏感性离子通道方面具有独特优势，特别是在相关的体内生物应用中。[63] 例如，Gao等人使用CuS纳米颗粒和特异性单克隆抗体相互作用开发了血管平滑肌中TRPV1信号的光热开关。[63a] 在1064 nm激光照射下，局部温度升高在几秒内触发TRPV1通道开放，导致大量Ca²⁺内流。小尺寸CuS纳米颗粒也可被包封在生物相容性CaCO₃纳米载体中，创建细胞内Ca²⁺级联反应器，通过光热激活TRPV1通道进行肿瘤治疗。[63b] 在酸性肿瘤微环境中，CaCO₃纳米载体分解释放足够的Ca²⁺，通过光热激活的TRPV1通道进入肿瘤细胞，破坏线粒体Ca²⁺稳态和功能，最终导致细胞凋亡。此外，硒化铜（Cu₂₋ₓSe）纳米晶体在1000 nm以上具有强吸收和优异的光热转换效率，在肿瘤光热治疗和光声成像方面显示出有前景的潜力。[70]

与无机对应物相比，有机光热剂具有增强的生物降解性和生物相容性，从而扩展了其临床应用。例如，ICG是一种FDA批准的小分子染料，在暴露于近红外光时表现出显著的光热效应和荧光发射，使其成为生物医学治疗和诊断应用的有力平台。最近，Chen等人开发了ICG胶束，在808 nm激光照射下表现出高效的光热转换和荧光发射，用于TRPV1介导的神经刺激。[65]

半导体聚合物纳米颗粒（SPN）由于其可调的光学性质和优异的生物相容性，已成为光热应用的有力平台。[52a] 最近，Li等人开发了一种半导体聚合物纳米点（SPNbc），在808 nm激光照射下表现出超快光热响应（约0.1秒），用于TRPV1介导的体外神经元激活。[66] 此外，一种名为MINDS（深脑刺激大分子红外纳米换能器）的纳米材料由聚（苯并双噻唑-alt-乙烯）核心和PLGA-PEG壳组成，在1064 nm激光照射下实现了小鼠深脑刺激。[11b]

### 3.3 磁热纳米材料

磁场可穿透生物组织而无明显衰减，使其成为深部组织应用的有前景的刺激方式。磁热纳米材料可在交变磁场作用下产生局部热量，激活TRPV1通道。这些纳米材料通常由磁性核心（如Fe₃O₄）和生物相容性涂层组成，以提高稳定性和靶向能力。

铁蛋白是一种天然存在的铁储存蛋白，可在交变磁场作用下产生热量。[13a] 最近的研究表明，铁蛋白纳米颗粒可通过磁热效应激活TRPV1通道，实现无线深部脑刺激。[74a] 此外，Fe₃O₄纳米颗粒已被广泛研究用于磁热激活TRPV1。例如，Chen等人开发了涂有聚丙烯酸-PEG（PAA-PEG）的Fe₃O₄纳米颗粒，在交变磁场作用下实现了小鼠深部脑刺激。[74b] 此外，聚（马来酸酐-alt-1-辛烯）-PEG（PMAO-PEG）包覆的Fe₃O₄纳米颗粒已被用于缓解小鼠帕金森样症状。[74c]

除Fe₃O₄外，其他磁性纳米材料如Co₀.₂₄Fe₂.₇₆O₄和CoFe₂O₄@MnFe₂O₄核壳纳米颗粒也已被开发用于TRPV1激活。[75,78] 这些纳米材料在交变磁场作用下表现出高效的磁热转换，实现了对TRPV1通道的无线远程控制。

### 3.4 其他纳米材料

除上述类别外，某些纳米材料可通过产生活性氧（ROS）、一氧化氮（NO）或机械力来激活TRPV1通道。例如，某些纳米材料可通过电化学反应产生NO，激活TRPV1通道。[6c] 此外，磁性纳米颗粒可在交变磁场作用下产生机械力，激活机械敏感性TRPV1通道。[79] 此外，某些纳米材料可在刺激下产生ROS，通过氧化应激机制激活TRPV1通道。[40]

## 4. 生物医学应用

### 4.1 神经刺激

TRPV1在感觉神经元中高度表达，使其成为神经调节的有前景的靶点。纳米材料介导的TRPV1激活可实现精确、非侵入性的神经刺激，具有深部组织穿透能力。例如，光热纳米材料（如金纳米棒和CuS纳米颗粒）已被用于通过近红外光激活TRPV1通道，实现无线神经刺激。[61,63] 此外，磁性纳米材料（如Fe₃O₄纳米颗粒和铁蛋白）已被用于通过交变磁场激活TRPV1通道，实现深部脑刺激。[13,74]

### 4.2 神经系统疾病治疗

TRPV1参与多种神经系统疾病的病理过程，包括帕金森病、阿尔茨海默病和癫痫。纳米材料介导的TRPV1调控为这些疾病的治疗提供了新策略。例如，Cu₂₋ₓSe纳米颗粒已被用于通过光热激活TRPV1通道治疗小鼠帕金森病。[71] 此外，Fe₃O₄纳米颗粒已被用于通过磁热激活TRPV1通道缓解小鼠帕金森样症状。[74b]

### 4.3 癌症治疗

TRPV1在多种癌细胞中表达，使其成为癌症治疗的有前景的靶点。纳米材料介导的TRPV1激活可通过诱导Ca²⁺过载和细胞凋亡来实现癌症治疗。例如，SPN-C（载辣椒素的半导体聚合物纳米颗粒）已被用于通过光热激活TRPV1通道实现癌症治疗。[53] 此外，CSPN（通过硫缩酮连接子偶联辣椒素的半导体聚合物纳米颗粒）已被用于荧光成像引导的光控Ca²⁺过载癌症治疗。[54]

### 4.4 代谢性疾病治疗

TRPV1参与代谢调节，包括血糖调节和能量代谢。纳米材料介导的TRPV1调控为代谢性疾病的治疗提供了新策略。例如，铁蛋白纳米颗粒已被用于通过磁热激活TRPV1通道调节小鼠血浆葡萄糖。[13a]

### 4.5 心血管疾病治疗

TRPV1在心血管系统中表达，参与血管张力和心脏功能的调节。纳米材料介导的TRPV1调控为心血管疾病的治疗提供了新策略。例如，CuS纳米颗粒已被用于通过光热激活TRPV1通道减轻小鼠动脉粥样硬化。[63a] 此外，铂纳米颗粒壳已被用于通过光热激活TRPV1通道预防犬室性心律失常。[62]

## 5. 挑战与未来展望

尽管纳米材料介导的TRPV1调控在生物医学应用中取得了显著进展，但仍面临若干挑战。首先，纳米材料的生物安全性需要进一步评估，包括长期毒性和免疫原性。其次，纳米材料的靶向递送效率需要提高，以减少脱靶效应。第三，纳米材料的刺激响应性需要优化，以实现更精确的时空调控。第四，纳米材料的临床转化需要克服监管和制造方面的挑战。

未来的研究方向包括：开发具有更高生物相容性和靶向能力的新型纳米材料；探索多种刺激模式的协同作用以实现更精确的TRPV1调控；研究TRPV1在不同疾病中的具体作用机制；以及推进纳米材料介导的TRPV1调控策略的临床转化。

总之，纳米材料介导的TRPV1调控为多种疾病的治疗提供了有前景的策略。随着纳米技术和生物医学的不断发展，这一领域有望在未来取得更多突破性进展。

我们利用两亲性嵌段共聚物开发了可生物降解的吲哚菁绿（ICG）胶束，展现出良好的稳定性、生物相容性和光热效应[65]。这些胶束通过TRPV1抗体识别靶向特定神经细胞膜，并在808 nm近红外光照射下实现TRPV1通道的远程激活。尽管取得上述进展，基于ICG的纳米材料仍存在光热转换效率相对较低且吸收光谱较窄（在1000 nm以内）的问题，限制了其在某些应用中的潜力。为解决这一问题，研究人员设计并合成了一系列具有高光热转换效率和可调近红外吸收波长的有机半导体聚合物纳米颗粒，用于分子成像、无创生物激活及先进治疗[11b,52a,66]。Wu等人开发了一种大分子换能器，其核心为半导体聚合物，外壳为两亲性聚合物，粒径约为40 nm，在1064 nm处的光热转换效率高达71%[11b]。这些特性使其能够在1064 nm激光照射下（入射功率密度为10 mW mm⁻²），以最小热损伤实现对活体小鼠中表达TRPV1神经元的远程激活。

3.3 磁热纳米材料磁场因其与生物分子相互作用弱且能深入穿透机体，适用于远程刺激。磁性纳米材料在交变磁场作用下通过磁滞耗散热量，成为高效的外源刺激换能器。磁性纳米材料的合成技术成熟，可精确调控其尺寸、形貌、组成和结构，广泛应用于磁共振成像和磁热治疗等生物医学领域[72]。 Fe₃O₄纳米颗粒备受关注，尤其已有FDA批准产品上市[73]，表明其在磁遗传学中具有应用潜力（表3）。在交变磁场作用下，Fe₃O₄纳米颗粒产热，激活TRPV1通道，触发神经元广泛且可逆的放电[13a,74]。这些粒径约20 nm的纳米颗粒可通过表面修饰适应多种生物应用。掺杂Mn或Co等过渡金属可增强其磁热性能，进一步优化TRPV1激活效果[75]。例如，用Co取代Fe₃O₄会破坏d轨道简并性，导致更强的自旋-轨道耦合、更高的磁各向异性和更宽的磁滞回线[75b]。超小MnFe₂O₄纳米颗粒（6 nm）的水分散液可在符合FDA标准的射频场（40 MHz，8.4 G）下迅速升温[75a]。当与链霉亲和素偶联后，这些纳米颗粒可定位于特定细胞膜，通过局部加热激活TRPV1通道，实现对秀丽隐杆线虫（C. elegans）的磁热神经调控。此外，硬磁相与软磁相之间的交换耦合作用是调控磁性的有效策略[76]。核壳工程可在单一纳米颗粒内实现硬磁与软磁组分的耦合，最大化比功率耗散并提升磁热转换效率[77]。Munshi等人合成了核壳结构磁性纳米颗粒（CoFe₂O₄@MnFe₂O₄），其中核径为8.0±1.0 nm，壳厚为2.25 nm，可在清醒、自由活动的小鼠中实现稳健且可重复的磁热激活运动行为[78]。内源性铁蛋白亦可将交变磁场转化为热量，从而激活TRPV1通道[13a,79]。铁蛋白是由轻链和重链组成的异源多聚体，其内部形成约5–12 nm的顺磁性氧化铁核心[80]，在射频场作用下通过奈尔弛豫和布朗运动产热。目前存在两种典型的基于铁蛋白的TRPV1激活策略：一是共表达嵌合型抗GFP-TRPV1与GFP标记的铁蛋白，通过GFP介导连接TRPV1与铁蛋白[13b,79a]；二是将TRPV1与激肽原-1的铁蛋白结合域融合，促使内源性铁蛋白铁离子重新分布至离子通道（FeRIC系统）[79b]。2012年，Stanley等人证实射频场可加热胞内铁蛋白，激活TRPV1通道，使前胰岛素释放量增加约67%，效果与外源Fe₃O₄纳米颗粒相当[13a]。他们还构建了基于胞内合成氧化铁纳米颗粒的基因编码系统，用于远程调控基因表达[39]。该系统不仅可控制工程化干细胞中Ca²⁺内流及关键蛋白表达，还能在小鼠模型中重复调节血浆胰岛素和血糖水平。此外，Hutson等人发现，将表达TRPV1-FeRIC的鸡胚心脏神经嵴细胞暴露于射频场，可模拟人类先天性心脏病症状[79b]。然而，射频场与铁蛋白如何影响TRPV1通道的机制仍存在争议[81]。

3.4 其他纳米材料多种一氧化氮（NO）纳米调节剂已被开发，可通过协调突触可塑性和神经分泌来特异性调控神经元（表4）。通常，NO供体被整合至纳米载体中，靶向病灶部位，并在特定刺激下产生NO以激活TRPV1[82]。一个典型例子是Wang等人开发的在近红外光刺激下释放NO的纳米平台。该平台采用聚多巴胺包覆的空心CuS纳米颗粒[82a]。在808 nm激光照射下，聚多巴胺层产生光生电子，触发NO供体的光化学分解，释放NO，进而激活TRPV1通道。此外，Anikeeva等人设计了Fe₃S₄纳米簇，可在温和电场下催化亚硝酸钠生成NO[83]。该方法可实现局部NO生成，并通过电压调控释放动力学，激活对NO敏感的TRPV1通道。将这类电催化纳米簇集成到多材料纤维中，可扩展其在体内NO介导的神经元操控应用，例如在小鼠腹侧被盖区及兴奋性投射中诱导可控神经元兴奋。研究人员还开发了一种全可降解的原电池系统，用于原位电化学生成NO以调控细胞行为[84]。在NaNO₂溶液存在下，生成的NO可打开HEK293T细胞膜上的TRPV1通道，触发钙离子内流。这种原位NO生成策略为深入研究NO相关生物过程及治疗方法提供了新途径。有趣的是，活性氧（ROS）和氧化脂质也可激活TRPV1通道，并增强其对热或辣椒素的敏感性[85]。近期研究表明，射频场可诱导内源性铁蛋白产生ROS，进而激活TRPV1通道（表4）[86]。该过程依赖于铁蛋白介导的细胞内不稳定铁池增加。释放的铁离子参与化学反应生成H₂O₂和氧化脂质，激活与铁蛋白偶联的TRPV1通道，增强Ca²⁺内流。然而，过量ROS会导致氧化应激，威胁神经元和胶质细胞，可能促进神经退行性疾病发展[87]。因此，能清除ROS的纳米材料有望用于治疗缺血性卒中等疾病[88]。当相邻颗粒沿磁场方向排列时，铁蛋白氧化铁纳米颗粒可将外源磁场转化为机械力[89]。TRPV1与机械敏感的非选择性阳离子通道TRPV4具有40%的氨基酸序列同源性，后者可被膜张力或直接机械力激活[90]。Stanley等人提出并验证了外源磁场是否可通过作用于铁蛋白对TRPV1施加机械力[13b]。与射频场加热不同，静磁场用于对铁蛋白偶联的TRPV1施加机械力。在HEK细胞上方移动标准永磁体可激活铁蛋白偶联的TRPV1，证实TRPV1通道对机械力具有响应性。

4. 生物医学应用 4.1 神经调控 TRPV1广泛分布于哺乳动物外周神经系统，包括背根神经节、三叉神经节神经元、神经末梢及角膜，作为内在热敏离子通道精确调控神经元内Ca²⁺水平。TRPV1激活导致胞内Ca²⁺浓度升高，触发神经末梢释放炎症介质和神经递质以传递信号。功能纳米材料在响应外源刺激（如磁场和光）产生局部热方面至关重要。纳米材料介导的神经调控，尤其是深脑区调控，已成为理解神经通讯的有力工具，并有望用于帕金森病等神经系统疾病的诊断和治疗[9]。磁热神经调控最早于2010年在体外和秀丽隐杆线虫中实现[75a]，近年已扩展至小鼠和大鼠模型[74a,d,78]。早期研究使用麻醉动物[74a]，后续研究则在自由活动的小鼠中诱发非自主行为[78]。纳米颗粒的表面修饰对于增强其体内生物相容性及实现与细胞膜上离子通道的靶向相互作用至关重要。根据应用场景，纳米颗粒可直接注射至特定脑区或器官[74d,78]。例如，Chen等人通过慢病毒递送TRPV1使小鼠腹侧被盖区兴奋性神经元对热敏感，四周后将Fe₃O₄纳米颗粒局部注射至同一区域[74a]。暴露于交变磁场（15 kA m⁻¹，500 kHz）可诱导神经元兴奋，表现为即刻早期基因c-fos表达上调（图4a）。然而，由于产热较慢，磁热神经调控通常需数十秒才能引发Ca²⁺内流增加[75a,78,79c]，可能超过神经元放电的时间动力学范围。相比之下，光热神经调控可在毫秒级时间尺度内激活TRPV1[61b,66,91]，无需磁线圈的空间限制，即可操控自由活动动物的行为（图4b）。近期研究表明，通过TRPV1激活的光热神经调控可使盲鼠残余光感受体细胞体及离体人视网膜对近红外光敏感[61e]。研究人员在视网膜变性小鼠模型中表达TRPV1通道，使原本对光不敏感的视网膜锥细胞在近红外光刺激下活性增强，进而激活神经节细胞层神经元和皮层神经元，最终使小鼠表现出习得性光驱动行为（图4c）。 TRPV1也是治疗神经退行性疾病的有效靶点[92]。近期研究强调，磁热和光热纳米材料介导的TRPV1调控在治疗帕金森病方面具有潜力[71,74b]。例如，Yuan等人利用Cu₂₋ₓSe纳米颗粒激活小胶质细胞中的TRPV1通道，显著增强自噬，促进α-突触核蛋白清除，从而改善帕金森病症状[71]。在1064 nm激光照射下，局部产热激活TRPV1通道，引发Ca²⁺内流，触发ATG5和Ca²⁺/CaMKK2/AMPK/mTOR信号通路，促进吞噬作用和α-突触核蛋白降解（图4d）。结果，帕金森病小鼠的运动能力显著改善，关键标志物如酪氨酸羟化酶、离子钙结合接头蛋白1、胶质纤维酸性蛋白和pSer129-α-syn水平恢复至与健康小鼠相当。

4.2 癌症 TRPV1通道在多种侵袭性肿瘤中高表达，如乳腺癌、肺癌、肝细胞癌、结直肠癌、胰腺癌和胶质母细胞瘤[93]。胞质游离Ca²⁺是癌症的关键调控因子，影响增殖、分化和基因转录等下游过程。因此，TRPV1激活诱导Ca²⁺内流，可能扰乱细胞内病理生理事件，引发癌细胞死亡。与大多数通过细胞器非特异性诱导细胞凋亡的纳米药物不同，纳米材料介导的TRPV1调控可特异性作用于高表达TRPV1的细胞膜，启动癌细胞凋亡。这些纳米材料的典型作用是作为激动剂的递送载体，通过外部刺激或肿瘤微环境响应控制其释放，以激活TRPV1通道用于癌症治疗[10b,53,54,58,60,94]。近红外光可高效触发纳米材料释放辣椒素（图5a），迅速提高细胞微环境中辣椒素浓度[53]。辣椒素持续激活TRPV1通道，导致Ca²⁺超载和线粒体膜电位去极化，随后细胞色素c释放，激活caspase-3，最终诱导胶质瘤细胞凋亡。此外，某些纳米材料可在近红外光照射下在细胞膜周围产生局部热用于癌症治疗[63b]。温度升高激活TRPV1通道，诱导Ca²⁺内流，破坏线粒体Ca²⁺稳态，导致功能障碍，进而引发胶质瘤细胞凋亡（图5b）。值得注意的是，这种热激活TRPV1机制不同于传统光热疗法，后者通过局部热效应直接破坏肿瘤细胞[95]。纳米材料介导的TRPV1调控可增强肿瘤对多种疗法的敏感性，如光动力治疗[59]、化学动力治疗[82a]和放疗[59,82b]。例如，Wang等人开发了一种双通道Ca²⁺纳米调节剂（CAP-P-NO），将辣椒素和NO基团整合至自组装肽中，通过诱导内源性Ca²⁺重分布实现肿瘤放射增敏[82b]。在酸性且富含谷胱甘肽的肿瘤微环境中，辣椒素和NO被释放，分别激活TRPV1和兰尼碱受体，导致细胞外Ca²⁺内流和内质网Ca²⁺释放。肿瘤细胞内高水平Ca²⁺破坏细胞器功能，引起广泛转录组变化，包括放疗抵抗相关基因下调，从而增强胰腺癌和患者来源肝肿瘤的放射敏感性（图5c）。免疫治疗不仅可激活免疫细胞控制原发肿瘤生长，还可形成免疫记忆细胞以防止转移和复发[96]。TRPV1通道可影响热休克蛋白70（HSP70）和转化生长因子β（TGFβ）的表达[97]，提示其在治疗过程中调控癌细胞自我防御行为中可能发挥作用。近期研究表明，纳米材料介导的TRPV1阻断可通过高效调控HSF1，选择性抑制应激性HSP70和TGFβ1，从而增强对高度恶性肿瘤的热免疫治疗效果（图5d）[63c]。在近红外光照射下，负载ICG/TRPV1拮抗剂的聚合物纳米颗粒对多种原发性、转移性和复发性肿瘤表现出显著抗肿瘤疗效。TRPV1阻断抑制HSF1核转位并下调TGFβ1，导致细胞外基质降解，改善抗PD-L1抗体和免疫细胞向纤维化和免疫抑制性肿瘤的浸润，实现协同热免疫治疗。

4.3 心血管疾病 TRPV1亦广泛分布于心血管系统，包括心肌、心肌细胞、血管内皮细胞和平滑肌细胞[98]。新证据强调TRPV1在心血管健康中的关键作用，包括调节脂质代谢和能量平衡、减少泡沫细胞形成、诱导自噬、减轻血管内皮损伤和抑制炎症[98a]。血管活性介质对TRPV1功能的调控及其对交感神经的影响有助于控制血管收缩和舒张，从而影响高血压发展[99]。此外，TRPV1通道激活在动脉粥样硬化动物模型中表现出保护作用[100]。鉴于其在心血管疾病中的广泛参与，本节重点介绍纳米材料介导的TRPV1调控在治疗动脉粥样硬化和血栓形成方面的治疗潜力[63a,101]。这可通过TRPV1在动脉粥样硬化中的固有调控功能或产生溶栓生物分子实现。例如，Gao等人开发了偶联TRPV1抗体的CuS纳米颗粒，可特异性靶向血管平滑肌细胞[63a]。在1064 nm激光照射下，局部产热打开TRPV1通道，诱导Ca²⁺内流。随后Ca²⁺-AMPK信号通路激活，增加胆固醇外流、增强自噬并减少泡沫细胞形成，最终减轻高脂饮食喂养小鼠的动脉粥样硬化病变（图6a）。Zhang等人通过整合代谢聚糖工程与纳米材料介导的TRPV1激活，远程控制尿激酶型纤溶酶原激活物（uPA）表达，实现溶栓治疗效果（图6b）[101b]。光热纳米换能器将近红外光转化为热量，打开TRPV1通道，触发合成信号通路，按需分泌uPA用于溶栓治疗。将抗炎和调脂药物（如阿托伐他汀）与纳米材料介导的TRPV1调控联合使用，可进一步提高疗效[101c]。此外，心肌缺血常导致急性室性心律失常，增加急性心肌梗死及时有效治疗的难度[102]。近期研究表明，光热纳米材料介导的自主神经系统调控在预防心肌缺血及后续心肌缺血-再灌注损伤方面具有潜力（图6c）[62]。在1064 nm激光照射下，光热纳米换能器分别激活温度敏感的TRPV1和TREK1通道，导致副交感神经激活和交感神经抑制。在雄性犬模型中，这种光热自主神经调控方法被证明可有效稳定心脏电生理，减少心肌缺血-再灌注损伤和心肌缺血期间的室性心律失常。

4.4 代谢性疾病 TRPV1功能失调与1型和2型糖尿病的发展相关[103]。Lee等人对高脂饮食（HFD）喂养的TRPV1敲除小鼠和野生型小鼠进行代谢研究，评估胰岛素和瘦素水平[104]。他们发现TRPV1缺陷加剧了HFD和衰老相关的肥胖和胰岛素抵抗，表明TRPV1在调节葡萄糖代谢和肥胖方面具有重要益处。此外，给肥胖小鼠喂食辣椒素可降低空腹血糖水平、脂肪堆积、胰岛素和瘦素水平，增强脂肪酸氧化，并显著减轻炎症和代谢紊乱[105]。近期，纳米材料介导的TRPV1调控在治疗代谢性疾病方面显示出潜力。 Jeffrey等人探索了利用外源性铁磁性纳米颗粒或内源性铁蛋白纳米颗粒进行磁热激活TRPV1[13,79a]。当暴露于低频无线电波时，Ca²⁺内流刺激由Ca²⁺敏感启动子驱动的工程化胰岛素基因表达，有效控制血糖水平（图7a）。最初，他们使用偶联抗His抗体的氧化铁纳米颗粒特异性结合带有胞外His×6表位标签的TRPV1通道。但由于纳米颗粒内化，需重复注射以实现长期血糖调控[13a]。为解决该问题，他们利用基因编码的内源性铁蛋白纳米颗粒结合TRPV1通道[13b]。他们采用三种策略：直接共表达TRPV1与铁蛋白、共表达TRPV1与融合细胞膜定位信号的铁蛋白，以及共表达N端修饰抗GFP抗体的TRPV1与GFP-铁蛋白融合蛋白。此外，他们基于相同的抗GFP–TRPV1 WT或突变体/GFP–铁蛋白系统构建了TRPV1突变体，激活时诱导Cl⁻内流，从而远程激活或抑制下丘脑葡萄糖敏感神经元，双向调节血糖水平（图7b）[79a]。双激活钙通道TRPV1和TRPA1可通过促进胰高血糖素样肽（GLP-1）分泌精确调控血糖稳态。例如，Li等人开发了一种仿生近红外纳米平台，将小肠内分泌细胞膜包覆于共轭寡聚物纳米颗粒表面[106]。在808 nm激光照射下，这些仿生纳米颗粒有效产生活性氧（ROS），从而激活小肠内分泌细胞中热敏感的TRPV1和ROS敏感的TRPA1通道，促进Ca²⁺内流，刺激GLP-1分泌，最终调节小鼠血糖（图7c）。肠道刺激可通过肠-脑轴传递，在调节代谢稳态中发挥关键作用。例如，Mac等人开发了一种自供电颗粒刺激系统，用于无创治疗肥胖相关代谢紊乱[107]。该创新系统由TRPV1激动剂和压电BaTiO₃颗粒组成。口服后，这些颗粒靶向辣椒素敏感的神经末梢，并响应胃蠕动产生微弱电信号。这种刺激激活迷走神经传入纤维，导致食物摄入减少、代谢率增加，最终改善小鼠饮食性肥胖（图7d）。

5. 挑战与展望在复杂生物环境中，生物界面的稳定性对于维持一致性能至关重要。这些进展的关键前提是确保纳米材料的生物安全性。虽然某些材料如吲哚菁绿（ICG）和Fe₃O₄纳米颗粒已获得FDA批准，但仍需进一步优化以提高其在TRPV1调控中的疗效。具体而言，调整其性质可增强与靶细胞的相互作用，同时最小化脱靶效应。临床上通常优选小于5 nm的纳米材料，因其在体内长期积累的风险较低[114]。然而，它们可能载药量有限，对特定肿瘤的被动靶向效率降低。因此，选择和设计纳米材料需仔细权衡治疗效果最大化和副作用最小化。对急性和慢性应用中的安全性、疗效和生物毒性进行全面评估，对于将这些创新从实验室推向临床至关重要。纳米材料介导的TRPV1调控原理可拓展至其他离子通道，为多种疾病的靶向治疗提供通用平台。通过利用不同离子通道的独特激活机制，我们可为特定生物医学应用设计定制化纳米材料。总之，纳米材料介导的TRPV1调控具有巨大且变革性的潜力。随着我们不断完善这些技术并应对现有挑战，我们正站在精准医学新时代的门槛上，靶向、无创的离子通道调控有望彻底改变多种疾病的治疗和管理方式。

纳米材料介导的TRPV1调控处于生物医学创新的前沿，为在深层组织中激活和抑制TRPV1通道提供了前所未有的精确性。这种方法有望在各种疾病中实现无创和靶向治疗干预。尽管取得了相当大的进展，但用于TRPV1调控的功能纳米材料的发展仍处于初期阶段，呈现出充满挑战和机遇的前景。

当前研究强调了纳米载体提高TRPV1激动剂（如辣椒素）生物利用度和半衰期的潜力。然而，传统纳米载体通常存在载药量和包封效率有限的问题，需要高剂量（表1）。自组装治疗性化合物形成纳米药物的出现可能通过实现100%的包封效率和最小化副作用来彻底改变这一领域。例如，辣椒素-BODIPY偶联物已证明能够自组装成纳米聚集体，显著降低前列腺癌治疗中所需的有效剂量。

除了辣椒素和热等传统TRPV1激活剂外，其他刺激物如低pH值和各种内源性脂质也显示出TRPV1激活的功效。这拓宽了设计多功能纳米材料的视野。例如，pH响应型纳米调节剂可以精确调节特定细胞膜周围的局部pH值，从而有效触发TRPV1通道。此外，设计整合多种激活机制（如pH敏感性、热响应和辣椒素释放）的纳米材料可以为研究TRPV1相关的生理和病理过程提供新方法。

尽管光热和磁热纳米材料在可控TRPV1激活方面具有巨大潜力，但它们也带来了一些挑战。一个主要问题是过热风险，可能会对周围组织造成损伤，特别是神经系统等敏感区域。这些材料还可能无意中激活其他受体或蛋白质，导致脱靶效应。另一个问题是热休克蛋白的过度表达可能干扰正常细胞功能和应激反应。为避免这些问题，关键是要提高这些纳米材料的转换效率，并在应用过程中实时监测温度分布，确保使用过程中的安全性和精确性。此外，光的穿透深度和金属植入患者中磁场应用的实用性也构成重大挑战。或者，超声波和X射线具有深层组织穿透性和操作灵活性，在临床环境中得到广泛应用。超声波和X射线响应纳米材料在生物成像、生物传感和癌症治疗方面的最新发展为TRPV1调控开辟了新的维度。设计对这些刺激响应的纳米材料可以产生热和机械力或释放TRPV1激动剂和拮抗剂，为无创治疗开辟新途径。

对于这些技术的临床转化，必须解决几个关键挑战。实现细胞特异性控制和确保外部刺激的精确、局部递送对于有效治疗结果至关重要。此外，增强