Optimized Bionic Drug Delivery Inducing Immunogenic Cell Death and cGAS-STING Pathway Activation for Enhanced Photochemotherapy-Driven Immunotherapy in Prostate Cancer

Prostate cancer (PCa) presents a challenging disease as it is often characterized as an immunologically “cold” tumor, leading to suboptimal outcomes with current immunotherapeutic approaches in clinical settings. Photodynamic therapy (PDT) harnesses reactive oxygen species generated by photosensitizers (PSs) to disrupt intracellular redox equilibrium. This process induces DNA damage in both the mitochondria and nucleus, activating the process of immunogenic cell death (ICD) and cGAS-STING pathway. Ultimately, this cascade of events leads to the initiation of antitumor immune responses. Nevertheless, existing PSs face challenges, including suboptimal tumor targeting, aggregation-induced quenching, and insufficient oxygen levels in tumor regions. To this end, a versatile bionic nanoplatform (M-TPNPs), has been designed for the simultaneous delivery of the aggregation-induced emission PS TPAQ-Py-PF6 and paclitaxel (PTX). The cell membrane camouflage of the nanoplatform leads to its remarkable abilities in tumor targeting and cellular internalization. Upon laser irradiation, the utilization of TPAQ-Py-PF6 in conjunction with PTX showcases a notable and enhanced synergistic antitumor impact. Additionally, the nanoplatform has the capability to initiate the cGAS-STING pathway, leading to the generation of cytokines. The presence of damage-associated molecular patterns (DAMPs) induces ICD and collaborates with these aforementioned cytokines, leading to the recruitment and facilitation of dendritic cells (DCs) maturation. Consequently, this elicits a systemic immune response against tumors. In summary, this promising strategy highlights the use of a multifunctional biomimetic nanoplatform, combining chemotherapy, PDT, and immunotherapy to enhance the effectiveness of anti-tumor treatment.