Injectable microgel-assembled hydrogel for synergistic photothermal-chemotherapy via melanin-mediated inflammation modulation

Abstract Malignant tumors pose a major threat to human health. Photothermal therapy (PTT) has gained extensive attention for its ability to rapidly ablate tumors via localized hyperthermia. However, monotherapy with PTT often yields suboptimal outcomes due to irregular tumor margins and indistinct boundaries between healthy and necrotic tissues. Additional challenges include overheating-induced inflammation and the need for safe, efficient photothermal agents. To address these limitations, an injectable photothermal hydrogel, named HPCS/MP, was developed through a microgel assembly strategy using polyethylene glycol-melanin microgels and hydroxypropyl chitosan (HPCS). DOX·HCl was incorporated into the gel matrix to enable combined photothermal-chemotherapy. Within this system, melanin acts not only as an effective photothermal converter but also as a structural component regulating hydrogel properties. The HPCS/MP hydrogel exhibits thermosensitive gelation at body temperature, allowing rapid formation upon intratumoral injection, and displays pH-responsive behavior in the tumor microenvironment. Leveraging the photothermal and anti-inflammatory capabilities of melanin, along with the chemotherapeutic effect of DOX·HCl, the composite hydrogel demonstrated effective tumor suppression and inflammation regulation in vivo. Moreover, DOX·HCl release can be precisely controlled using an external laser. Thus, the HPCS/MP injectable hydrogel system presents a promising strategy for combined tumor therapy by integrating efficient antitumor action with inflammation modulation.