pH-responsive biomimetic liposomes enhance targeted immunotherapy of bladder cancer.

Bladder cancer is one of the most prevalent malignant tumors of the urinary system, and its high incidence and mortality seriously threaten human health. Although emerging immunotherapies have achieved remarkable results in bladder cancer, they still face great challenges such as immune tolerance and low response rates in clinical practice. Therefore, to overcome immunotherapy resistance and low response rates, we designed and prepared a pH-responsive biomimetic liposome (LP) encapsulating the lymphocyte activation gene 3 protein (FGFR) inhibitor erdafitinib using the thin-film hydration method, yielding erdafitinib-loaded liposomes (ELPs). Meanwhile, bladder cancer cell membranes (M) were hybridized onto the liposomal surface to construct biomimetic liposomes (MELPs), thereby endowing the liposomes with homologous tumor-targeting capability through membrane-mediated recognition. The study demonstrated that MELP could directly target the FGFR receptor to trigger ferroptosis in bladder cancer cells through the JAK2-STAT3-GPX4 signaling pathway, as well as promote macrophage polarization and dendritic cell maturation in vitro, thereby stimulating antitumor immune responses. MELP exhibited good biosafety and bladder tumor-targeting ability based on biodistribution in vivo. Moreover, MELP combined with the LAG-3 antibody not only effectively inhibited bladder tumor growth and metastasis but also remodeled the tumor immune microenvironment by promoting dendritic cell maturation, enhancing CD8+ T lymphocyte infiltration, and inducing M1-type macrophage polarization in bladder tumors, which can convert immunologically "cold" tumors into "hot" tumors, thereby potentiating the therapeutic efficacy of immune checkpoint blockade and significantly prolonging survival. Therefore, the combination of MELP and LAG-3 antibody can effectively enhance targeted immunotherapy against bladder tumors, which can also provide a novel strategy for bladder cancer.