Hybrid lipoplex co-delivering siPD-L1/miR-140-5p reverses T cell exhaustion via post-transcriptional regulation for in situ photothermal vaccination

vaccine through a local MPTT, which co-delivered silencing PD-L1 siRNA (siPD-L1) and microRNA-140-5p (miR-140-5p) (AR/si/mi). It promoted dendritic cell maturation, enhanced TAA uptake, and robust local immune priming. Approximately 90% inhibition of PD-L1 mRNA was achieved using the AR/si/mi system. In murine bilateral melanoma models, intratumoral administration of hybrid lipoplexes not only ablated primary tumors (95.8% inhibition) but also elicited systemic antitumor immunity, effectively suppressing untreated distant tumors (99.6% inhibition). This combination treatment mitigated MPTT-induced PD-L1 upregulation and alleviated T cell exhaustion. Collectively, these findings demonstrate a synergistic strategy that enhances photothermal immunotherapy through the co-delivery of siRNA and miRNA to suppress PD-L1, enabling potent and systemic antitumor responses.