Nanoparticles‐Mediated Modulation of TRP Channels: Advances and Therapeutic Potential

TL;DR

This review explores how nanoparticles can control TRP ion channels, offering new ways to develop minimally invasive therapies for various diseases.

Contribution

The paper systematically reviews the therapeutic potential of nanoparticle-mediated modulation of TRP channels.

Findings

Nanoparticles can activate TRP channels using optical, electrical, and magnetic signals.

TRP channels are key targets for controlling cell signaling in physiological and pathological contexts.

Advances in nanotechnology can lead to precise and non-invasive therapeutic strategies.

Abstract

Nanoparticles have emerged as promising tools for targeting and activating ion channels that serve as transducers for external signals. Their nanoscale dimensions enable targeted activation of ion channels at the cellular or subcellular level, offering unprecedented opportunities to control biological cell signaling. Recent works have demonstrated nanoparticle‐mediated stimulation based on optical, electrical, and magnetic external signals, highlighting their potential to serve as minimally invasive therapeutics. In addition, there is an increasing need to identify relevant ion channels and their physiological role in advancing emerging nanotechnologies. The transient receptor potential (TRP) family, including prominent members such as the TRPV (vanilloid), TRPM (Melastatin), and TRPA (ankyrin), plays critical roles in physiological functions, such as temperature sensation, pain perception, and mechanical stimulus detection, and can be controlled via nanoparticle signaling. This review highlights the properties and roles of dominant TRP family members in different organs and positions them as relevant targets for novel technologies. Leveraging the knowledge of nanoparticle properties with recent advances in pharmacology and disease treatments that target TRP family members will enhance the development of novel nano‐biotechnologies to control cell signaling.

Nanoparticle‐mediated modulation of TRP channels, highlighting the interplay between external stimuli, tailored nanomaterials, and TRP channel activation across a range of physiological contexts. This review examines the roles of TRP channels in cellular signaling and disease, providing insights into how advances in nanotechnology can facilitate precise, minimally invasive therapeutic strategies. Created in https://BioRender.com.

Figures

Timeline of findings on TRP ion channels and advances in nanoparticle technology. Created in BioRender. Rosenfeld, D. (2026) https://BioRender.com/bb2vie8.

Applications of various nanoparticles categorized by stimulation mechanisms: Photothermal, optogenetics, magnetothermal, and mechanical stimulation. Created in BioRender. Rosenfeld, D. (2026) https://BioRender.com/1pi9so8.

Tables

TABLE 1. TRP channels localization, function and activation mechanisms.

TRP channel	Function	Localization	Activation mechanisms	References
TRPM3	Heat hypersensitivity, spontaneous pain, insulin release, ureter motility	Sensory neurons (dorsal root ganglia), retina, kidney, brain (cerebellar Purkinje neurons, oligodendrocytes)	Heat, pregnenolone sulfate, osmotic pressure, modulated by Mg2+ and Ca2+, enhanced by phosphatidylinositol 4,5‐bisphosphate	(Grimm et al. 2003; Su et al. 2021; Badheka et al. 2015; Held and Tóth 2021; Hoffmann et al. 2010; Zamudio‐Bulcock et al. 2011; Dyment et al. 2019; Becker et al. 2023; Krügel et al. 2017)
TRPA1	Pain, itch, inflammation, regulation of macrophage/T cell activity, modulation of serotonin release	Sensory neurons, epithelial cells, keratinocytes, enterochromaffin cells, endothelium, CNS neurons	Noxious cold, pungent compounds, H2O2, reactive oxygen species, Zn2+, pH changes, endogenous signals (e.g., 4‐hydroxy‐2‐nonenal)	(Andersson et al. 2011; Dhaka et al. 2006; Patil et al. 2023; Bautista et al. 2006)
TRPV1	Pain, thermo‐sensation, itch, cancer cell proliferation	Peripheral sensory neurons, dorsal root ganglia, trigeminal ganglia, vagal ganglia, arteriolar smooth muscles, gastrointestinal tract, urinary epithelial cells, pancreatic B cells, eosinophils	Heat (≥ 41.5°C), vanilloid compounds (capsaicin, resiniferatoxin), acidic pH (≤ 5.9), inflammatory mediators (e.g., ATP, glutamate, PGE2)	(Cao et al. 2013; Escelsior, Sterlini, Belvederi Murri, et al. 2020; Gavva et al. 2004)
TRPV4	Thermo‐sensation, mechanical stimuli, flow‐dependent K+ secretion, cellular responses to metabolites	Brain, sensory neurons, kidneys, bladder, skin, skeletal muscle, ciliated epithelia, vascular smooth muscle	Temperatures above 27°C, mechanical stimuli, hypotonicity, metabolites of arachidonic acid, PKC, PKA, 5′,6′‐epoxyeicosatrienoic acids	(Satheesh et al. 2016; Chen and Sonkusare 2020; Hattori et al. 2021)

TABLE 2. Disorders involving TRP ion channels.

Disorder	TRP channel role and therapeutic implications	References
Neuropathic pain (Diabetic neuropathy, postherpetic neuralgia, sciatica)	TRPV1: Activated by heat and capsaicin; modulates pain. Capsaicin patches reduce pain. TRPA1: Activated by chemical compounds; involved in pain persistence. Antagonists reduce pain but require caution due to potential excitotoxicity.	(van Hecke et al. 2014; Lantéri‐Minet and Perrot 2019; Eberhardt et al. 2017)
Inflammatory diseases (RA, IBD)	TRPV1: Activates inflammation and cytokine production; contributes to inflammation via NF‐κB activation.	(Liao et al. 2024; Mazor et al. 2024)
Cardiovascular disorders (Hypertension, heart failure, atherosclerosis)	TRPV1: Regulates cardiac function; targeting may protect against ischemic injury. TRPA1: Activated by oxidative stress; modulators could prevent cardiac fibrosis. TRPM3: Regulates vascular tone.	(Jiang et al. 2018; Lu et al. 2016)
Neurodegenerative disorders (Alzheimer's, Parkinson's, Ms)	TRPV1: Protects against Aβ toxicity; activation supports neuroprotection. TRPA1: Involved in neuroinflammation; targeting may reduce inflammation‐related damage.	(Shigetomi et al. 2013; Yuan et al. 2022)
Respiratory disorders (COPD, asthma, chronic cough)	TRPA1: Leads to bronchoconstriction; antagonists reduce cough. TRPV1: Modulates cough and airway tone; antagonists may alleviate symptoms. TRPV4: Involved in airway inflammation; inhibitors reduce bronchoconstriction.	(Marsh et al. 2020; Balestrini et al. 2021; Li et al. 2025)
Skin conditions (AD, psoriasis, chronic itch)	TRPA1: Involved in non‐histaminergic itch; inhibitors reduce chronic itch. TRPV1: Mediates histaminergic pruritus and skin aging; capsaicin‐based therapies alleviate symptoms.	(Feng et al. 2017; Wilson et al. 2013; Liu, Escalera, et al. 2013; Tang et al. 2022; Kusumaningrum et al. 2018)
Renal disorders (AKI, CKD)	TRPV1: Regulates excretion and protects against fibrosis; agonists reduce renal dysfunction. TRPV4: Involved in osmoregulation; inhibition alleviates AKI injury.	(Soni et al. 2019; Zhu et al. 2005; Li and Wang 2008; Wang and Wang 2011)
Metabolic diseases (Obesity, insulin resistance)	TRPV1: Regulates insulin secretion; agonists improve glucose metabolism. TRPA1: Modulates glucose and lipid profiles. TRPV4: Enhances insulin secretion; may help manage endothelial dysfunction.	(Li et al. 2022; Zsombok and Derbenev 2016; Lee and Yeo 2015)
Psychiatric disorders (PTSD, anxiety, addiction)	TRPV1: Modulates stress response and emotional regulation; targeting may improve PTSD therapy and anxiety outcomes.	(Escelsior, Sterlini, Murri, et al. 2020; Schumacher et al. 2019; Liu et al. 2022)

Full text

Introduction

1

The role of TRP channels in sensory perception and their potential as analgesic targets was first foreshadowed in 1969 (Cosens and Manning 1969), later attributed to a mutation in the transient receptor potential (TRP) gene (Minke et al. 1975). In 1989, TRP was shown to be a transmembrane ion channel, establishing TRP channels as potential targets for analgesic drugs (Montell and Rubin 1989). TRP channels are crucial for detecting environmental stimuli, including temperature, pain, and chemical signals, and play a role in sensory perception and physiological responses (Story 2006; Zhang et al. 2023). Their regulation of calcium ions (Ca^2+^) homeostasis links them to diseases involving protein misfolding and disrupted ion dynamics. However, therapeutic targeting of TRP channels in the nervous system is hindered by limited modulator specificity, poor blood–brain barrier permeability, and off‐target effects (Mulier et al. 2017; Thapak et al. 2020).

Nanomaterials, defined as 1–100 nm in size, exhibit unique properties at the nanoscale due to their size and surface‐to‐volume ratio. Common types of nanomaterials employed for receptor activation and cell signaling modulation include gold nanoparticles (AuNPs), silica nanoparticles, quantum dots, and magnetic nanoparticles (MNPs). Because TRP channels are activated by sensory stimuli, nanomaterials can be designed to precisely control their activity through thermal, mechanical, and optical means (Hescham et al. 2021; Rosenfeld et al. 2020). Figure 1 outlines the history of the discovery of TRP channels and the integration of nanomaterials towards their activation.

Timeline of findings on TRP ion channels and advances in nanoparticle technology. Created in BioRender. Rosenfeld, D. (2026) https://BioRender.com/bb2vie8.

This review consolidates current knowledge on the role of TRP channels in various disorders and presents recent discoveries relating to the expression of TRP channels across different organs and diseases. It focuses on four TRP channels that were demonstrated to be activated by nanomaterials which hold potential as therapeutic approaches and presents the mechanisms of action and applications of the relevant nanoparticles.

Properties and Roles of TRP Channels

2

The TRP family in mammals comprises 28 members classified into seven subfamilies according to amino acid sequence homology: TRPA (ankyrin), TRPC (canonical), TRPM (melastatin), TRPML (mucolipin), TRPN (no mechanoreceptor potential C), TRPP (polycystin), and TRPV (vanilloid). The channels are located on the plasma membrane with a distinct crystal structure (Zhang et al. 2023). While originally identified for their role in calcium ions (Ca^2+^) transport, many TRP channels are also permeable to other ions such as magnesium (Mg^2+^), sodium (Na^+^), and potassium (K^+^) (Zhang et al. 2023). The channels respond to diverse stimuli, including temperature shifts, natural chemicals, toxins, mechanical forces, and endogenous signals produced during injury or inflammation, thereby contributing to thermo‐sensation, vision, taste, pain, and itch (Zhang et al. 2023). The next sections summarize the primary properties of four ion channels: TRPM3, TRPV1, TRPA1, and TRPV4 (Table 1).

TRPM3

2.1

TRPM3 is a heat‐sensitive, Ca^2+^‐ and Mn^2+^‐permeable ion channel, predominantly expressed in dorsal root ganglion (DRG) sensory neurons, where it contributes to thermal hypersensitivity and nociception post‐nerve injury (Grimm et al. 2003; Su et al. 2021). In addition to heat, it is activated by the neurosteroid pregnenolone sulfate, the synthetic agonist CIM‐0216, and osmotic stress (Becker et al. 2023; Vangeel et al. 2020), and its activity is modulated by intracellular Mg^2+^ and Ca^2+^ (inhibitory) and phosphatidylinositol 4,5‐bisphosphate (stimulatory) (Badheka et al. 2015; Held and Tóth 2021). Mutations in TRPM3 have been implicated in developmental disorders, including epilepsy (Dyment et al. 2019). Common inhibitors of TRPM3 include baclofen, isosakuranetin, the Gβγ subunit of trimeric G‐proteins, and primidone (Becker et al. 2023; Krügel et al. 2017). While the pharmacological activation of TRPM3 has been thoroughly studied, it was also claimed that noxious heat with an increase of 7°C–10°C above physiological conditions can induce its activation (Vriens and Voets 2018).

TRPA1

2.2

TRPA1 is a Ca^2+^‐permeable cation channel activated by diverse stimuli, including noxious cold, pungent compounds, hydrogen peroxide, Zn^2+^, acidic pH, and endogenous aldehydes like 4‐hydroxy‐2‐nonenal (Bandell et al. 2004). In Drosophila and snakes, TRPA1 was found to be heat‐sensitive, whereas in mammals, it is considered cold‐sensitive (Neely et al. 2011). Moreover, it was demonstrated that TRPA1 responds to cold‐induced oxidative stress and not directly to cold (Miyake et al. 2016). It is widely expressed in neurons, keratinocytes, and epithelial cells, and is involved in pain, itch, and inflammatory signaling (Bautista et al. 2006; Patil et al. 2023). Agonists include allyl isothiocyanate (AITC), cinnamaldehyde, allicin, acrolein, and byproducts of oxidative stress. Its antagonists HC‐030031, A‐967079, AP18, and SZV‐1287 effectively reduce mechanical hyperalgesia and inflammation (Bandell et al. 2004).

TRPV1

2.3

TRPV1 is a non‐selective cation channel permeable to Na^+^, K^+^, and Ca^2+^, and is involved in pain perception and thermo‐sensation. It is activated by temperatures ≥ 41.5°C, vanilloid compounds (e.g., capsaicin, resiniferatoxin) and pH < 5.9 (Cao et al. 2013). Highly expressed in sensory neurons, dorsal root and trigeminal ganglia, and smooth muscle, TRPV1 also plays roles in cell communication and behavioral modulation. Therapeutically, capsaicin and resiniferatoxin initially activate TRPV1 before inducing desensitization, resulting in reduced pain signals. This underpins the clinical use of topical capsaicin formulations, including high‐dose patches for neuropathic pain. TRPV1 antagonists, such as capsazepine and ruthenium red, inhibit channel activity and show promise in models of neuropathic and inflammatory pain (Cao et al. 2013).

TRPV4

2.4

TRPV4 is a calcium‐permeable ion channel activated by mechanical stimuli, osmotic stress, and moderate temperatures (24°C–34°C) (Shibasaki et al. 2015). While it is considered a mechanically‐gated ion channel, the mechanism of activation varies between cells. For example, hypoosmotic change from 200 to 400 mOsm activates TRPV4‐mediated calcium influx in chondrocytes (O'Conor et al. 2014), while mechanical stretching of bladder tissue evokes ATP release (Roberts et al. 2020). TRPV4 plays a key role in regulation of flow‐dependent potassium secretion in the kidney and is widely expressed in the brain, sensory neurons, bladder, and skin. Mutations in TRPV4 have been linked to skeletal dysplasia and cardiovascular disorders (Nilius and Voets 2013). Several TRPV4 agonists have been identified, including endogenous molecules, like 5,6‐epoxyeicosatrienoic acid, and synthetic compounds, such as 4α‐PDD, RN‐1747, and GSK1016790A, which are commonly used in research (Nilius and Voets 2013). A novel TRPV4 agonist has demonstrated a cartilage‐protective impact in osteoarthritis models without inducing systemic toxicity, highlighting its therapeutic potential (Hattori et al. 2021).

Disorders Involving TRP Channels

3

TRP channels are implicated in a wide range of diseases and disorders. The following sections outline the primary conditions associated with TRP channel dysfunction and detail the specific roles these ion channels play in disease pathogenesis. Key findings from the literature are summarized in Table 2. The disorders summarized in this section are also intended to highlight potential opportunities for the development of future technologies aimed at targeting TRP channels for therapeutic intervention.

Recent studies have demonstrated that the presence of TRP channels in a given tissue or cell type does not guarantee responsiveness to stimuli by specific cells (Kudsi et al. 2022). For instance, TRPA1 and TRPV1 are detected in general in cardiac tissue; they fail to respond to their typical agonists, such as capsaicin and AITC, when applied directly to cardiomyocytes (Hoebart et al. 2021). Similarly, TRPV4 and other TRP channels are expressed in the retina, but remain largely insensitive to classical activating stimuli (Toft‐Bertelsen and MacAulay 2021). Moreover, studies have demonstrated that although TRPM3, TRPA1, and TRPV1 are co‐expressed on dermal arteries, mainly TRPM3 mediates agonist‐specific responses, such as pregnenolone sulfate–induced vasodilation (Toft‐Bertelsen and MacAulay 2021). Collectively, these observations underscore the importance of distinguishing expression from functional relevance when evaluating TRP channels in disease contexts.

Neuropathic Pain

3.1

Neuropathic pain arises from lesions or diseases affecting the somatosensory system and affects approximately 7%–10% of the population (van Hecke et al. 2014). TRP channels, particularly TRPV1 and TRPA1, are implicated in the maintenance of pathological nociceptor sensitization rather than in physiological pain detection. The clinical efficacy of capsaicin patches, which reduce TRPV1 responsiveness and deplete substance P, results in prolonged analgesia (Lantéri‐Minet and Perrot 2019). TRPA1 antagonists attenuate neuropathic pain by limiting maladaptive channel over activation, whereas TRPA1 agonists, such as acetaminophen's reactive metabolite, induce neuronal desensitization. However, the narrow therapeutic window of these agents highlights the need for controlled and localized modulation strategies (Eberhardt et al. 2017).

Inflammatory Diseases

3.2

TRP channels, including TRPV1 and TRPA1, are expressed in immune and stromal cells, where they modulate inflammatory signaling pathways. TRPA1 mediates inflammatory responses to environmental irritants and proalgesic agents, linking exogenous chemical exposure to tissue inflammation. In rheumatoid arthritis (RA), TRPV1 and TRPA1 activity influence inflammatory pain, and TRPV1 has emerged as a potential therapeutic target due to its regulating role in inflammatory signaling in joint tissues (Liao et al. 2024). In inflammatory bowel disease (IBD), TRPV1 contributes to neurogenic inflammation as demonstrated by reduced gut inflammation and visceral hypersensitivity upon selective inhibition or silencing of TRPV1‐expressing fibers (Mazor et al. 2024).

Cardiovascular Diseases

3.3

Several TRP channels, including TRPV1, TRPV2, TRPA1, and TRPM3, regulate vascular and myocardial responses under pathological conditions. TRPV1 exerts cardioprotective effects, promoting recovery following ischemic injury by reducing apoptosis through phosphoinositide 3‐kinase/protein kinase B (PI3K/Akt) signaling, but also contributes to dysfunction when aberrantly activated during maladaptive remodeling (Jiang et al. 2018). TRPA1 activation has been shown to limit ischemia–reperfusion injury within cardiac myocytes (Lu et al. 2016).

Neurodegenerative Disorders

3.4

TRP channels regulate calcium homeostasis, neuronal excitability, and inflammation, linking them to neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). TRPA1 mediates amyloid‐beta (Aβ)‐induced neuroinflammation through calcium entry in astrocytes (Shigetomi et al. 2013), and capsaicin consumption protects neurons from Aβ toxicity (Wang et al. 2020). In PD, TRPV1 contributes to calcium imbalance and neuronal stress or death, and its activation by capsaicin has shown neuroprotective effects via microglia autophagy (Yuan et al. 2022).

Respiratory Diseases

3.5

TRP channels play a central role in respiratory health, through their regulation of airway tone, cough reflexes, and inflammatory responses. TRPA1 serves as a key sensor in the airways, and its activation triggers bronchoconstriction, cough, and the release of proinflammatory mediators (Marsh et al. 2020). TRPV1 similarly influences airway tone and contributes to bronchoconstriction and inflammation, making it a potential target for management of respiratory illnesses (Balestrini et al. 2021).

Skin Conditions

3.6

TRP channels, particularly TRPA1 and TRPV1, are expressed in skin cells including keratinocytes and melanocytes, and their activation contributes to pruritus, skin barrier dysfunction, and inflammation (Feng et al. 2017). TRPA1 is activated by irritants and inflammatory mediators and is resistant to antihistamine, contributing to non‐histaminergic itch. TRPA1 knock‐out models show reduced chloroquine‐induced itch, suggesting that inhibitors could alleviate drug‐resistant pruritus (Wilson et al. 2013). In atopic dermatitis, TRPA1 expression is unregulated, and its inhibition reduces spontaneous scratching (Liu, Escalera, et al. 2013).

Visceral Disorders

3.7

TRP channels, particularly TRPV1 and TRPV4, are involved in kidney function and renal disorders, particularly osmoregulation, ion transport, and mechano‐sensation. In kidney regions, TRPV4 interacts with a sodium‐potassium‐chloride cotransporter essential for sodium reabsorption. Its demonstrated role in ischemia–reperfusion injury suggests that its inhibition could mitigate acute kidney injury (AKI) (Soni et al. 2019). TRPV1 channels act as low‐pressure baroreceptors in the renal pelvis, regulating neuropeptide release in response to mechanical stimulation (Zhu et al. 2005). Their activation increases glomerular filtration rate (GFR) and promotes sodium and water excretion (Li and Wang 2008). In chronic kidney disease, TRPV1 activation has been shown to reduce inflammation and fibrosis (Wang and Wang 2011). TRPV1 agonists protect against ischemia–reperfusion‐induced renal dysfunction, and their activation can improve outcomes in AKI (Soni et al. 2019). Moreover, TRPA1 was investigated as an activator of enterochromaffin cells and gastrointestinal function, and was linked to serotonin release and motility (Bellono et al. 2017; Nozawa et al. 2009).

Metabolic and Endocrine System Disorders

3.8

TRP channels regulate ion homeostasis and impact metabolic processes in obesity, insulin resistance, and hypertension (Lee and Yeo 2015; Li et al. 2022; Zsombok and Derbenev 2016). For example, TRPV1 regulates pancreatic β‐cell function and insulin secretion, and its knockout increases obesity and insulin resistance, suggesting its protective role in glucose metabolism (Li et al. 2022). Capsaicin‐mediated activation of TRPV1 improves endothelial function and insulin sensitivity, while TRPA1 influences glucose and lipid profiles and enhances insulin sensitivity (Zsombok and Derbenev 2016). TRPV1 activation also reduces atherosclerotic lesion formation and reduces cholesterol and triglyceride levels, while capsaicin activates bile acids to improve lipid metabolism (Lee and Yeo 2015). TRPV1 expression in the adrenal glands suggests its role in regulating hormone release and balance, particularly under stress conditions, and in coordinating cortisol release (Rosenfeld et al. 2020; Surkin et al. 2018).

Psychiatric Disorders

3.9

TRPV1 channels have been implicated in emotional responses such as anxiety. Modulation of TRPV1 offers novel treatment options due to its interactions with the hypothalamic–pituitary–adrenal (HPA) axis and neurotransmitter systems (Escelsior, Sterlini, Murri, et al. 2020). In post‐traumatic stress disorder (PTSD), abnormal cortisol levels indicate alterations in HPA axis activity and are associated with heightened stress sensitivity and fear responses (Schumacher et al. 2019). Activation of TRPV1 channels within adrenal cells increases glucocorticoid release, while blocking them reduces cortisol secretion (Liu et al. 2022).

Nanoparticles for TRP Channel Activation

4

Nanoparticles have become invaluable in remote and selective activation of TRP channels due to their precision, control, and broad potential applications in biomedicine. Using nanoparticles, these channels can be selectively stimulated through magnetic, optical, or mechanical stimuli. This section explores the different types of nanoparticles used in TRP channel research, their activation mechanisms, targeting strategies, advantages, risks, and potential for advancing therapies in the central and peripheral nervous systems (Figure 2).

Applications of various nanoparticles categorized by stimulation mechanisms: Photothermal, optogenetics, magnetothermal, and mechanical stimulation. Created in BioRender. Rosenfeld, D. (2026) https://BioRender.com/1pi9so8.

Nanoparticle Activation Methods

4.1

Nanoparticles‐Mediated Magnetic Hyperthermia

4.1.1

Magnetic nanoparticles (MNPs) are widely explored for their ability to generate controllable, localized heat under alternating magnetic fields (AMFs). When the particle size is below 30 nm, MNPs typically form a single magnetic domain and exhibit super paramagnetic behavior. In the absence of an external field, their magnetic moments are randomly oriented, resulting in no net magnetization. Upon exposure to a magnetic field, the moments align along the field direction, dissipating energy as heat primarily through Brownian and Néel relaxation processes. The efficiency of this heating depends on the AMF frequency and the intrinsic properties of the nanoparticles, such as size, anisotropy, and surface characteristics (Bedanta and Kleemann 2009; Izydorzak et al. 2012; Li et al. 2010).

In a magnetized particle, the magnetic anisotropy energy is derived from spin‐orbital interactions between electrons and is responsible for maintaining the spins oriented in a particular direction. The energy associated with this anisotropy for each particle is expressed in Equation (1):

$$[eqn]$$

where Keff is the anisotropy constant, V is the particle volume, and θ is the angle between the magnetization vector and the easy axis of the particle. The energy barrier (up to KeffV) determines the threshold for moment reversal and decreases as V decreases. Equation (2) describes the total power (P) dissipated from the materials:

$$[eqn]$$

where f is frequency and ΔU is the hysteresis loop area in the applied field (Hergt et al. 1998). When magnetized in a single direction, it doesn't return to its original state after field removal and an opposite field is needed to reverse its magnetization. This lag results in energy loss, manifested as heat. The dissipated heat is the basis of magnetic hyperthermia.

The heat generated under AMF is estimated by Equation (3):

$$[eqn]$$

where f is frequency, H is the field strength, χ is the imaginary part of magnetic susceptibility, and μ₀ is the permeability of free space (Deatsch and Evans 2014; Rosensweig 2002). In Néel relaxation, the magnetic moment realigns internally while the particle remains fixed (Néel 1953). In Brownian relaxation, the magnetic moment stays fixed relative to the crystal axis while the particle rotates (Brown 1963).

The heating efficiency of MNPs under AMF is calculated as the specific absorption rate (SAR) or specific loss power (SLP), defined as P per unit of mass and is given by Equations (4) and (5).

$$[eqn]$$ $$[eqn]$$

where ω = 2πf is the angular frequency, H is the field strength, and χ₀ is the magnetic susceptibility.

While magnetic hyperthermia was initially developed as a cancer treatment via increase of the temperature inside the tumor to destroy cancer cells (Farzin et al. 2020), local elevation of the temperature in the cell surroundings can also activate heat receptors, including heat‐sensitive ion channels, such as TRPV1, with a physiologically relevant temperature threshold. Huang et al. employed 6 nm superparamagnetic manganese ferrite (MnFe_2_O_4_) nanoparticles targeted to the cell membrane to activate the TRPV1 ion channel in neuronal cells under a 40 MHz radiofrequency magnetic field (Huang et al. 2010). In addition, Stanley et al. demonstrated gene expression regulation via calcium signaling induced by the activation of TRPV1 (Stanley et al. 2012). Chen et al. reported on Fe_3_O_4_ MNPs‐driven activation of TRPV1 activation in genetically modified cells, which was later translated to a rodent model for wireless deep brain stimulation (Chen et al. 2013, 2015). This opened avenues for wireless neuronal control, studied behavioral studies and Parkinson's models (Hescham et al. 2021; Munshi et al. 2017). The localized heating by MNPs has also been exploited to trigger controlled drug release for applications such as cancer therapy and neuromodulation (Attia et al. 2022; Fluksman et al. 2023). A recent report used capsaicin‐loaded MNPs to activate TRPV1 in hippocampal neurons (Santi et al. 2025).

Due to the broad expression of TRPV1 in deep organs, wireless schemes to control TRPV1 expression in non‐neuronal electrogenic cells are being developed to open new therapeutic avenues. One example is the control of stress hormone release by injection of MNPs into the adrenal gland and exposure to an AMF, which triggered calcium influx to adrenal cells in both the cortex and medulla, and subsequent rapid hormone release to the bloodstream (Rosenfeld et al. 2020). Moreover, magnetothermal activation via MNPs targeted specifically to TRPV1 showed efficacy in treating osteoarthritis through calcium signaling, reducing synovitis and knee pain (Lv et al. 2024). MNP‐activated TRPV1 effectively accelerated axonal growth in DRGs (Rosenfeld et al. 2022). A magnetothermal multiplexing approach can serve for selective triggering of TRP ion channels in neuronal cells (Moon et al. 2020; Sebesta et al. 2022). Advanced validation studies are still needed to confirm that the cells remain viable despite repeated thermal stimulation. This can be examined via development of 3D culture systems that replicate the cellular microenvironment and are essential for demonstrating the efficiency of magnetothermal stimulation (Midler et al. 2025; Shalom et al. 2025). It should be noted that calcium entry to cells via the ion channels can enhance calcium levels and potentially affect cell viability, with responses dependent on the duration, magnitude, and frequency of calcium influx (Stueber et al. 2017). Importantly, different cell types exhibit distinct sensitivities to calcium elevations and therefore, careful consideration of calcium dynamics is essential when designing calcium‐dependent nanomaterial‐based strategies for cellular activation (Kowaltowski et al. 2019).

Nanoparticles‐Mediated Optical Hyperthermia

4.1.2

Optical hyperthermia utilizes light energy to generate localized heat using plasmonic nanoparticles (NPs), typically made of noble metals including silver NPs (Ag NPs) or gold NPs (Au NPs) (Kosuda et al. 2016; Kreibig and Vollmer 1995). When these nanomaterials are excited by a light source at a wavelength resonating with the surface plasmons' oscillation, electronic absorption initially captures energy from the incident laser pulse. This is followed by electron–phonon thermalization, establishing an internal thermal equilibrium. Finally, heat diffusion to the surrounding environment increases the local temperature of the medium (Fratila and de la Fuente 2019; Underwood and Mulvaney 1994).

The required activation light can range from visible to near‐infrared (NIR) light, depending on the shape and size of the nanoparticles. For example, increasing the length‐to‐diameter ratio of gold nanorods (AuNRs) shifts the activation light from visible to the NIR wavelength. AuNR activation by NIR was utilized in various studies for high heating efficiency and penetration depth to activate TRPV1. AuNRs coated with a genetically cationized form of high‐density lipoprotein (HDL) were applied to bind to TRPV1‐expressing DRG cells and were then activated by pulsed laser irradiation at 532 nm (Nakatsuji et al. 2015). Neuronal silencing was recently achieved by targeting antibody‐functionalized gold NPs (AuNPs) to sensory neurons and delivering calcium channel blockers via the activation and opening of the TRPV1 channel. Silencing these neurons reduces neuropeptide release and modulates neuro‐immune interactions (Roversi et al. 2022). Remote activation of neurons via heat‐induced TRPV1 opening was also reported upon incorporation of AuNPs into micelle structures, which were subsequently activated using NIR light (Chen et al. 2022). A similar method used thermoresponsive polymers embedded with AuNRs for delivery of anesthetic agents (Zhou et al. 2018). AuNRs were also used to activate TRPV1 expressed in chondrocytes to suppress tissue inflammation and improve physical function and pain‐related to osteoarthritis (Li et al. 2024).

Gold shells were also shown to be useful for TRPV1 activation. In a recent study, Wu et al. used gold shells with a SiO_2_ core, conjugated to TRPV1 antibodies and β‐synuclein peptides, to activate TRPV1‐expressing dopaminergic neurons and induce dopamine release in a PD model (Wu et al. 2025).

Alternative NP platforms beyond noble metals also hold considerable therapeutic promise, for example, to be activated with NIR light with reduced attenuation in tissues. Among these, polymeric NPs such as polydopamine nanoparticles (PDA‐NPs), synthesized through the oxidative polymerization of dopamine or other catecholamines, have emerged as attractive candidates. PDA‐NPs activated under 808 nm laser irradiation excite unconjugated electrons, which later release heat through their relaxation process. Recent studies have focused on the photothermal effect of PDA‐NPs for cancer treatment (Liu, Ai, et al. 2013; Wu et al. 2023), drug delivery (Carmignani et al. 2024), and biomedical implants modification, and as therapeutic antioxidant agents (Battaglini et al. 2022, 2020; Lou et al. 2021; Yin et al. 2023). PDA‐NPs applied for TRPV1 activation resulted in pain suppression (Sun et al. 2025) and differentiation of mesenchymal stem cells (Dan et al. 2023). A recent study exploited a similar photothermal effect to trigger TRPV1 ion channel activity in Schwann cells for peripheral nerve regeneration (Hu et al. 2024).

NP‐Mediated Mechanical Stimulation

4.1.3

Mechanical stimuli induce cellular responses either by direct stimulation of mechanosensitive ion channels or by distortions of the membrane and cell structure (Glogauer et al. 1995; Wang et al. 1993). For example, TRPV4‐selective activation was previously demonstrated in neuronal cells (Wu et al. 2021). On‐chip design of MNPs with cortical neurons induced mechanical neuronal activation with nanomagnetic forces of 0.1–1 nN (Kunze et al. 2017; Landis and Kunze 2025). Moreover, smaller magnetic nano‐transducers in disc‐like shapes can convert low external magnetic fields (< 20 Hz), via vortex ground state. Such nanomaterials were demonstrated to apply torque on the cell membrane, resulting in activation of mechanosensitive ion channels and calcium influx in neurons and electrogenic cells (Beckham et al. 2025; Gomez et al. 2023; Gregurec et al. 2020). A similar‐shaped nanodisc fabricated together with additional piezoelectric materials generated sufficient voltage to activate voltage‐gated ion channels, rendering it sufficiently robust and efficient for activation of neuronal cells in vitro and in the brain (Kim et al. 2025).

NP‐Mediated Optical Stimulation via Optogenetics

4.1.4

Optogenetics utilizes light‐sensitive proteins (opsins) to modulate neuronal activity and investigate cellular functions with high spatiotemporal precision. The technique employs visible light in the range of 430–630 nm with tunable wavelength and intensity (All et al. 2019). Due to the limited tissue penetration of visible light, upconversion methods are being explored, which involve the use of lanthanide nanoparticles (LNPs), which absorb NIR light (~975 nm) and emit visible light (~543 nm); therefore, they can be combined with channelrhodopsins (ChRs), which are activated by visible light. This method enables deep brain stimulation without the need for invasive optical probes, demonstrating strong potential for studying neuronal networks and developing treatments for neurological disorders. However, several challenges remain, including optimization of the spectral properties of LNPs, compatibility with ChRs, and biosafety (Hososhima et al. 2015).

To improve precision, core‐shell upconversion nanoparticles (UCNPs) that emit specific visible wavelengths upon NIR excitation have been developed. Such UCNPs have been incorporated into biodegradable polylactic‐co‐glycolic acid (PLGA) scaffolds to create an implantable NIR‐sensitive optogenetics platform, which successfully activated ChR2‐expressing neurons, reducing the required light power and pulse duration while maintaining biocompatibility (Shah et al. 2015). This advancement significantly broadens the applicability of optogenetics for both basic research and therapeutic use.

Limitations and Barriers in Translation to Therapeutic Activation of TRP Channels

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NP‐based therapies targeting TRP channels have emerged as a promising therapeutic approach for a variety of medical conditions, including neurological, inflammatory, and pain‐related disorders. Through innovations in nanoparticle design, these technologies offer remote, controlled modulation of TRP channels, enabling more precise and effective therapeutic strategies. Yet challenges do exist, as discussed in this section. Future advancements relating nanoparticles and TRP channels are presented in Figure 1.

Toxicity is an important factor to consider, with the biocompatibility of some NPs remaining to be determined (Jaswal and Gupta 2023; Murphy et al. 2008; Zhang et al. 2022). Gene‐ and protein‐level interactions with the NPs can trigger inflammation, oxidative stress, and immune activation, causing tissue and cellular damage (Ouyang et al. 2020; Sukhanova et al. 2018). NP toxicity is also dictated by their shape, size, surface characteristics, and colloidal and chemical stability, which all impact NP internalization, stability, and aggregation under physiological conditions. NP toxicity is commonly assessed using in vitro cytotoxicity assays; however, these methods can be unreliable because NPs may interfere with assay components (Ettlinger et al. 2022). Additionally, washing steps required before analysis can bias measurements of cell death, and changes in cell morphology may be misidentified due to NPs obstructing optical signals.

Serum or biological fluid proteins can non‐specifically bind to NPs, resulting in formation of a protein corona on its surface, which affects its stability and delivery to specific targets, especially if it is functionalized for cell binding. Additionally, NP surface charge can influence clearance, with higher mobility measured for cationic versus anionic NPs, and higher stability for neutral NPs (Mitchell et al. 2021). In addition, NP diffusion or mobility through the bloodstream into other organs can result in off‐target effects and toxicity, as well as reduced effectiveness at the target (Mitchell et al. 2021; Sharma et al. 2018).

An additional factor that can limit NP applications is the type of signal used for NP activation. For example, AMFs can penetrate deep into the organ and should have a frequency‐amplitude limit of 5 × 10^9^ A/m, which can be assumed safe to surrounding tissues (Liu et al. 2020). However, other methods that rely on optical modulation or acoustic waves entail a trade‐off between penetration depth and resolution (Chen et al. 2017; Shahriari et al. 2020). The reproducibility of optical nanomaterials also poses challenges due to optical signal instability in biological environments and poor penetration into tissues (Li and Yin 2019). Methods that rely on thermal activation of heat‐sensitive ion channels require comprehensive assessment of heat distribution of the tissue to prevent off‐target heating. This can be effectively quantified by measuring the temperature increase inside the body during application of the external signal. However, thermal imaging within organs is challenging, especially when combined with AMF stimulation. To overcome these challenges, heat transfer simulation models that account for organ geometry, blood perfusion, NP heat dissipation, and the timing of stimulation have been adopted (Midler et al. 2025). MNP stimulation within the adrenal glands, repeated over six months with MNP inside the organ, resulted in no actual damage to the organ and physiological stability of the MNPs (Rosenfeld et al. 2020). Moreover, the heating rate across hyperthermia studies depends not only on the signal but also on the NP material and synthesis. For example, MNP synthesis, yielding magnetite particles, achieved a higher heating rate than previous syntheses, reducing the latency between AMF onset and neural response by several seconds (Chen et al. 2013, 2016).

One means of ensuring safer and more accurate NP‐based therapy is improved targeting of the NP to the cell population of interest. This can be achieved, for example, via antibody conjugations on the NP surface or magnetic guidance of the NP to the target site. However, high NP concentrations are often needed to achieve a sufficient effect (El‐Sayed et al. 2006; Gao et al. 2023; Kumar et al. 2008). In addition, surface chemistry is crucial for optimization of chronic organ stimulation, which will likely be needed to advance NP‐based therapies targeting TRP channels.

Despite the presented challenges in NP‐based therapies, multiple clinics are already implementing FDA‐approved iron oxide nanoparticles (Huang et al. 2022). For example, iron oxide NPs are intravenously injected as contrast agents for MRI and for anemia therapy in patients with chronic kidney disease (Long et al. 2024). Silica–gold nanoshells and spherical gold nanoparticles have also been approved by the FDA for cancer therapies (Boselli et al. 2024). However, the paucity of clinical applications stands in stark contrast to the extensive advances in nanoparticle design and characterization over the past two decades, highlighting a critical translational gap in this field.

Conclusion and Future Directions

6

Future research should focus on enhancing the specificity of TRP channels targeting to minimize off‐target effects and on exploration of nanoparticle‐channel interactions. Additionally, understanding the long‐term safety and biocompatibility of NPs will be crucial for their clinical translation.

Promising areas of research include the development of multifunctional nanoparticles that combine therapeutic and diagnostic capabilities, as well as personalized medicine approaches tailored based on patient‐specific TRP channel profiles. Furthermore, the integration of advanced imaging and drug delivery systems could improve NP‐based treatment strategies. Interdisciplinary collaborations between experts in materials science, biology, and medicine, along with sustained funding from both public and private sources, will be crucial to unlock the full potential of nanoparticle‐based therapies for TRP channel modulation.

This review discusses the role of TRP channels in disease and therapeutic strategies, identifies key knowledge gaps in their functional mechanisms, and highlights the potential of nanomaterial‐mediated technologies to modulate and activate TRP receptors. By integrating these perspectives, it opens new opportunities to advance nanoparticle‐based therapies through targeted modulation of TRP channels and paves the way for future research and innovative clinical applications.

Author Contributions

Karina A. Foster, Noy Mider, and Ori Shine: writing – original draft, writing – review and editing. Dekel Rosenfeld: conceptualization, writing – original draft, writing – review and editing, supervision, funding acquisition, investigation, resources.

Funding

This work was supported by D.R. acknowledges the support of the Zuckerman STEM Leadership Program, the Israel Science Foundation (2220/23 and 1048/23), the Ministry of Science, Technology, and Space, Israel (1001576214), and the European Research Council Horizon 2020 (MagGelGut, 101116555).

Conflicts of Interest

The authors declare no conflicts of interest.