Reprogramming Immunodeficiency in Lung Metastases via PD-L1 siRNA Delivery and Antigen Capture of Nanosponge-Mediated Dendritic Cell Modulation

Abstract

Infiltration of cytotoxic T lymphocytes into hypovascular metastases offers significant potential for suppressing even the most intractable metastatic tumors, with dendritic cells (DCs) serving as pivotal initiators of antitumor immune responses during immunotherapy. However, the immune-privileged nature of hypovascular lung metastases combined with the inherently low immunogenicity of tumor clusters poses substantial barriers to effective lymphocyte recruitment. Here, a pH-responsive lung metastatic-targeted catalyst containing the tumor penetration polymer (TP)/solid lipids (SL)-coated Prussian blue (TP-SL@PB)-enhanced PD-L1 siRNA delivery and self-cascade antigen capture is developed for reprogramming immunodeficiency. Intravenously injected TP-SL@PB accumulated in the blood vessel-poor lung metastases via the organ-selective targeting and charge conversion of TP. In tumor clusters, SL@PB exerts catalytic and lysosomal escape effects, easily enhancing siRNA delivery and thus downregulating PD-L1. Catalysis also promotes the release of tumor-associated antigens (TAAs), including neoantigens and damage-associated molecular patterns. Subsequently, both positive TPs and SLs on PBs can act as antigen sponges to deliver TAAs to dendritic cells, thereby inducing long-term immune activation. TP-SL@PB acts as a hypovascularized lung metastasis-penetrating catalytic nanosponge, selecting T cells to infiltrate metastases and enhance immunotherapy.