Mild Photothermal Therapy Combined with Capsaicin for Tumor Immunotherapy and Analgesia by Inhibiting TRPV1 Channels

Photothermal therapy (PTT) is a promising strategy for breast cancer treatment but is limited by hyperthermia-induced pain. Mild photothermal therapy (mPTT, 42-45 °C) offers a safer alternative, reducing adverse effects whereas enhancing therapeutic synergy. A complementary pain-relief strategy is the ablation of TRPV1-positive sensory nerve endings. Capsaicin (CAP) has both analgesic and immunotherapy-enhancing properties; however, its poor water solubility restricts clinical application. Manganese oxide (MnO₂) nanoflowers, with their large surface area, strong NIR-II photothermal performance, and capacity to remodel the tumor microenvironment (TME), provide a potential solution. In this study, CAP was loaded into MnO₂-SiO₂ composite nanoparticles (MSC NPs) to achieve immune-enhanced mPTT for concurrent tumor therapy and pain suppression. mPTT induced tumor cell damage through NIR-II photothermal effects, whereas CAP and MnO₂ enhance immunotherapy. CAP ablated TRPV1-expressing sensory nerve endings, establishing a dual-function platform that integrates tumor treatment with pain relief. This strategy represents a promising avenue for breast cancer management.