Plasma-based biomimetic antigen outpost synergizes with immune checkpoint blockade to enhance antitumor immunity via dual inhibition of SOCS1 and PD-L1 pathways in dendritic cells

A biomimetic antigen outpost is engineered to sustainably co-deliver tumor antigens, siSOCS1, and Mn 2+ adjuvant. • Plasma gel recruits DCs to the injection site, while CRT on nanovaccines acts as an "eat-me" signal to enhance antigen uptake. • SOCS1 silencing and PD-L1 blockade synergistically empower DCs to more effectively prime and activate cytotoxic T lymphocytes (CTLs). • PD-L1 blockade further protects activated CTLs from tumor cell-mediated exhaustion, enabling sustained tumor killing and potent antitumor immunity in TNBC models. Tumor vaccines represent a promising immunotherapy approach but are challenged by rapid systemic clearance, low immunogenicity, and various immunosuppressive mechanisms. To overcome these issues, we created a biomimetic antigen outpost system to enhance vaccine delivery and immune activation. This system uses cationic 1,2-dihydroxybenzene-modified poly- l -lysine to co-load small interfering RNA targeting cytokine-suppressing factor 1 (siSOCS1) and immunoadjuvant (Mn 2+ ) as the core. This core is further coated with calreticulin (CRT)-enriched tumor cell membranes to form a nanovaccine (CRTM/PBM siSOCS1 ), which is ultimately encapsulated in a plasma gel (PG@CRTM/PBM siSOCS1 ). This design prolongs the vaccine's in vivo retention, recruits dendritic cells (DCs) by simulating subcutaneous hemorrhage signals, and enhances effective antigen uptake through CRT-mediated “eat me” signals. Upon DC internalization, the nanovaccine undergoes non-lysosomal trafficking, avoiding siSOCS1 degradation. The efficient SOCS1 silencing alleviates intracellular immunosuppressive feedback and, together with synergistic DC activation by antigens and Mn 2+ , further promotes DC maturation and antigen cross-presentation. In a triple-negative breast cancer model, the combination with anti-PD-L1 antibody simultaneously blocked PD-L1 on both mature DCs and tumor cells, significantly enhancing cytotoxic T lymphocyte function at both the immune priming and effector stages, and demonstrating potent antitumor efficacy. This multi-level intervention strategy provides a promising platform for enhancing cancer immunotherapy. Download: Download high-res image (112KB) Download: Download full-size image