Active Lysosomal Nanoplatform for Ferroptosis-Enhanced Immunotherapy via Tumor Extracellular Matrix Remodeling

Abstract

The therapeutic efficacy of nanomedicines in solid tumors is often limited by rapid systemic clearance, dense extracellular matrix (ECM) barriers, poor tumor cell selectivity, and an immunosuppressive tumor microenvironment. Herein, we report an active lysosome-encapsulated hollow mesoporous Prussian blue nanoparticle platform that sequentially overcomes these challenges through prolonged circulation, ECM remodeling, tumor-targeted delivery, and immune modulation of the tumor microenvironment in a subcutaneous 4T1 tumor model. The lysosomal membrane enhances biocompatibility and circulation time, facilitating preferential tumor accumulation. Upon arrival, retained lysosomal hydrolases, including cathepsins B, K, L, and S, degrade ECM components, enabling deep nanoparticle penetration and immune cell infiltration. In the tumor parenchyma, lysosomal membrane encapsulation enhances cellular uptake, leading to iron overload and lipid peroxidation-driven ferroptosis, further amplified by nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy. Proteomic profiling revealed increased oxidative stress and local remodeling of the tumor immune microenvironment, corroborated by dendritic cell maturation, CD8+ T cell infiltration, and macrophage polarization. These effects collectively remodeled the immunosuppressive tumor niche. Compared with conventional biological membrane coatings such as red blood cell-derived vesicles, this lysosome-based system exhibits enhanced tumor accumulation, enzymatic functionality, and immunotherapeutic synergy. These findings highlight lysosome-encapsulated nanomedicine as a potential platform for ECM remodeling-facilitated immunotherapy with broad potential across therapeutic modalities.