Gatekeepers of Pain: A Scoping Review on How Nanoparticle Engineering Illuminates Selective Transient Receptor Potential Vanilloid 1 (TRPV1) Targeting

Conventional analgesics often provide limited relief for chronic pain and can cause systemic side effects. This scoping review aims to analyze mechanistic and bibliometric trends in nanoparticle-engineered delivery systems designed to selectively modulate transient receptor potential vanilloid 1 (TRPV1) receptors for precision chronic pain therapy; following PRISMA 2018 guidelines, the first 100 top-cited records from the Web of Science (WoS) Core Collection were organized in Microsoft Excel (Microsoft® Corp., Redmond, WA) and BibTeX (Oren Patashnik, Stanford University, Stanford, CA) for bibliometric analysis, with data also being qualitatively synthesized. Citation patterns were concentrated among a few leading researchers and institutions, highlighting the value of aligning with established funding bodies. Advanced polymeric and magnetic nanoparticles demonstrated the ability to cross the blood-brain barrier and selectively modulate TRPV1-mediated pain pathways. Nanoparticles carrying charged capsaicinoids improved bioavailability and reduced neuroinflammation relative to free capsaicin. Dose-dependent effects were consistently observed, as sustained low-dose release produced receptor desensitization and analgesia, while burst or high-dose delivery caused neuronal ablation. Surface-functionalized nanoparticles, particularly those with TRPV1-binding ligands or redox-responsive coatings, enhanced receptor specificity and reduced transient receptor potential ankyrin 1 (TRPA1) co-activation. Rationally engineered nanoparticles optimized for size, charge, ligand density, and release kinetics present a promising avenue for safer, more effective chronic pain therapies. By selectively modulating TRPV1 while mitigating thermoregulatory disruption, researchers can achieve long-lasting analgesia by prioritizing targeting precision to advance sustainable chronic pain treatments.