TRPV1 Activation via a Three-Stage Adaptive Heat-Absorbing Hydrogel Drives Neurovascular-Immune Coupling.

Abstract

Impaired neurovascular-immune coupling severely hampers chronic wound healing. Although the transient receptor potential vanilloid 1 (TRPV1) channel represents a promising therapeutic target, its therapeutic application remains limited by imprecise activation. Here, we developed a three-stage adaptive and heat-absorbing hydrogel (termed HMCG) that enables programmable and localized TRPV1 activation under near-infrared (NIR) irradiation. HMCG forms reversible boronate ester bonds between PVA and TSPBA, enabling a sol-aerosol-gel adaptive with sprayable handling, self-adaptation, and conformal coverage of complex wound topologies. This dynamic behavior ensures close biointerface contact and controlled thermal regulation during stimulation. Embedded Ca-gallic acid metal-organic frameworks (MOFs) act as photon-thermal converters, where ligand-metal charge transfer and π-π stacking drive rapid nonradiative relaxation, leading to efficient and controllable heat absorption. Brief NIR exposure triggers the sustained release of capsaicin and Ca²⁺, elevating the local temperature to 43°C, within the TRPV1 activation window and with a reduced risk of nonspecific thermal overstimulation. Together, the tri-stage adaptive design helps buffer heat, maintains topological adaptability, and synchronizes mild photothermal and biochemical cues. This controlled light-heat-chemical coupling supports the restoration of neurovascular-immune coupling and promotes tissue regeneration in diabetic skin lesion models, establishing a controlled, programmable platform for TRPV1-targeted regenerative therapy.