Hypoxia-Activated Paclitaxel Prodrug Combined with Dimeric Indocyanine Green for STING Activation and Reinvigorated Cancer Treatment

Combinational therapy has become a pivotal strategy in oncology due to its potential to overcome drug resistance and enhance therapeutic efficacy. Herein, we synthesized a hypoxia-responsive paclitaxel (PTX) prodrug (PA), which can assemble with dimeric indocyanine green (DICG) into PADI NPs in the absence of any adjuvants. PADI NPs possess enhanced colloidal stability and prolonged blood circulation, thus realizing preferential accumulation at the tumor site. In response to a hypoxic tumor microenvironment, PADI NPs undergo a reduction and self-elimination reaction to generate a PTX monomer and synchronously release DICG. Upon irradiation, the generated reactive oxygen species and hyperthermia of DICG not only cooperate with PTX-instructed chemotherapy to synergistically induce immunogenic cell death but also activate the cGAS–STING pathway, ultimately initiating a potent antitumor immune response. The in vivo experiments validated the combination of PTX chemotherapy and DICG phototherapy elicited robust antitumor immunity, realizing a better tumor treatment compared to commercial Abraxane. This hypoxia-responsive nanoplatform exemplifies a promising strategy for enhancing treatment precision and efficacy against tumors.