Chemomagnetic Capsaicin Delivery for TRPV1 Modulation in Chronic Pain and Neural Repair

Introduction: : Neuropathic pain is a severe and often debilitating condition affecting approximately 50 million people in the United States, frequently requiring long-term management. It arises from damage to the somatosensory system, resulting in heighted excitatory signaling and reduced inhibitory signaling–creating a hyperexcitable state often described by patients as intense burning or stabbing pain. Despite its prevalence, effective treatments remain limited. Current options rely heavily on opioids, which pose significant risks of addiction and systemic side effects. Capsaicin, a chemical derived from chili peppers, has emerged as a promising non-opioid analgesic. Its effects are mediated through binding to the transient receptor potential vanilloid 1 (TRPV1) channel located on sensory neurons. With continuous and prolonged exposure, TRPV1 becomes desensitized, producing sustained analgesia. However, clinical use of capsaicin is limited by poor solubility, rapid degradation, and low tissue retention. To address these challenges, nanoparticle encapsulation strategies have been explored, but most rely on passive diffusion, offering minimal control over the drug release. To overcome this limitation, we developed a magnetic field-controlled drug delivery system for capsaicin that enables precise, on-demand modulation of TRPV1 activity (Figure 1). This approach enables controlled drug release from an external source, offering targeted pain relief with reduced systemic exposure. In addition to analgesia, this system may promote nerve regeneration, offering a multifunctional platform for managing neuropathic pain.

Materials and

Methods: : Iron oxide magnetic nanoparticles (MNPs) were surface-functionalized via atom-transfer reverse polymerization (ATRP) to grow thermoresponsive poly (oligo (ethylene glycol) methyl ether methacrylate) (POEGMA) brushes, forming a nanoscale capsaicin reservoir. Upon exposure to an external alternating magnetic field (AMF, 27.3 mT, 250 kHz), MNPs undergo hysteresis power loss, generating localized heat. This heat triggers a thermodynamic phase transition in the POEGMA coating, resulting in a microdose release of capsaicin. Importantly, AMF-induced heating caused no measurable toxicity to primary hippocampal cultures. Nanoparticles were characterized by transmission electron microscopy (TEM) for morphology, dynamic light scattering (DLS) for size distribution, and Raman Spectroscopy to confirm chemistry. Capsaicin release kinetics were evaluated under passive and AMF-activated conditions. Primary hippocampal neurons isolated from newborn Sprague–Dawley rats were used to assess TRPV1 activation and desensitization via calcium imaging. Six experimental groups were studied: (i) Capsaicin, direct administration of capsaicin serving as positive control; (ii) AMFs (−) MNPs-C (−), intact cells serving as negative control; (iii) AMFs (+) MNPs-C (−), control of AMFs in the absence of the capsaicin; (iv) AMFs (−) MNPs-C (+), control of MNPs-C formulation in the absence of AMFs; (v) AMFs (+) MNPs-P (+), control of the treatment using unloaded MNPs; and (vi) AMFs (+) MNPs-C (+), the treatment group. LIVE/DEAD and ROS generation assays were performed to assess biocompatibility. Imaging data were analyzed using ImageJ and statistical analysis was performed through a one-way ANOVA.

Results, Conclusions, and Discussions:: We demonstrated that MNPs can be successfully functionalized with thermoresponsive POEGMA polymer brushes, as confirmed by TEM, DLS and Raman spectroscopy. These polymer-coated MNPs remain stable at both room and physiological temperatures. Upon exposure to AMFs, the MNPs undergo hysteresis heating, triggering a phase transition in the POEGMA brush that enables precise, on-demand release of capsaicin, achieving ~98% release of the total drug cargo. This controlled release strategy represents a significant improvement over traditional formulations reliant on passive diffusion. We evaluated the bioactivity of released capsaicin using calcium imaging in primary hippocampal neurons. A single dose of AMF-triggered capsaicin release activated TRPV1 in over 75% of neurons, while repeated doses induced TRPV1 desensitization in over 90%, achieving analgesic effects consistent with capsaicin’s therapeutic mechanism. Additionally, in ND7/23 cells, capsaicin delivery promoted morphological signs of neuronal differentiation, suggesting potential regenerative benefits. Importantly, our LIVE/DEAD and ROS assays confirmed minimal cytotoxicity ( < 30%), indicating that this delivery system is biocompatible and does not cause significant neuronal damage. Together, these findings validate that POEGMA-functionalized MNPs enable remote-controlled, repeatable, and localized neuromodulation without compromising neuronal viability. This chemomagnetic platform provides a novel method to deliver hydrophobic compounds with precision. It holds promise as a non-opioid treatment for chronic pain by enabling repeatable TRPV1 modulation while minimizing system exposure and side effects. Furthermore, the system’s ability to promote neuronal differentiation introduces the possibility for combined pain relief and nerve regeneration. By enabling magnetically triggered, localized delivery of hydrophobic drugs like capsaicin, this platform not only offers potential for improved chronic pain treatments but also lays the foundation for more precise, nonopioid targets, transforming therapeutic approaches in chronic pain.

Acknowledgements and/or References (Optional):: This work has been supported by the National Science Foundation Career Award #2044713.