Photo-manipulated polyunsaturated fatty acid-doped liposomal hydrogel for flexible photoimmunotherapy

Despite the synergy of immune checkpoint blockade (ICB) therapy and photodynamic therapy (PDT) holds great promise as countermeasures against breast cancer, exploring long-term or flexible short-time therapeutic strategies in "cold" tumors remains a great challenge. Here, we present a polyunsaturated fatty acid-doped liposomal hydrogel Lp(DHA)@CP Gel loaded with photosensitizer chlorin e6 (Ce6) and programmed death-ligand 1 antibody (alpha PD-L1) for flexible local photoimmunotherapy with merely singledosed administration. The presence of polyunsaturated fatty acid (docosahexaenoic acid, DHA) doped in particle membrane endows liposomes with flexibly reactive oxygen species (ROS)-responsive release capability, which was attributed to the presence of abundant unsaturated groups. The alpha PD-L1 was repeatedly induced to in situ release in response to the PDT under photo-exposure. The immunogenic cell death (ICD) effect of PDT evoked "cold" breast tumor to "hot" one, and then assisted the cascade released alpha PD-L1 to synergistically boost the immunotherapy. After a single dose of peritumoral administration of Lp(DHA)@CP Gel, the on-demand treatment can maximize patient compliance and safety by adjusting therapeutic behaviors via a photo on-off switch. This work presents a flexible medication platform, showing promise in improving the objective response rate of ICB therapy and minimizing its systemic toxicity. (c) 2024 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.