Multicomponent nanoassembly integrating photosensitizer and Astragalus polysaccharide adjuvant for amplified photoimmunotherapy via hypoxia adaptation disruption

Photoimmunotherapy (PIT) employs photosensitizers that generate reactive oxygen species (ROS) under near-infrared laser irradiation to induce immunogenic cell death (ICD) and trigger systemic antitumor immunity. However, the hypoxic conditions within tumors markedly reduce photosensitization efficiency and therapeutic efficacy. Moreover, insufficient immune activation together with the profoundly suppressive tumor immune microenvironment further compromises treatment outcomes. Given these challenges, it is imperative to develop an integrated therapeutic platform capable of effectively overcoming these limitations. Here, a responsive delivery system has been developed that utilizes ROS and incorporates the immunomodulatory agent Astragalus polysaccharide (APS). Hydrophobic rapamycin (RAPA) is linked to the APS backbone through an ROS-sensitive thioether TK bond, forming the amphiphilic APS-TK-RAPA (ATKR) conjugate. Subsequently, the photosensitizer 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH) is integrated into the system. The designed ATKR conjugate carrier facilitates the maturation of dendritic cells (DCs), effectively captures antigens released during PDT, and enhances antigen presentation. This further amplifies the adaptive immune response mediated by the APS-based carrier, thereby strengthening antitumor efficacy. In summary, ATKR with superior biocompatibility effectively surmounts the delivery challenges of hydrophobic photosensitizers. Moreover, it offers a promising nanoscale platform to address the critical issue of hypoxia in photodynamic therapy for cancer, serving as an effective inducer for augmenting immune responses.