Biomimetic Dual‐Engine Nanodisruptor Degrades Extracellular Matrix and Hijacks TAM2 to Unlock Deep Immune Infiltration in HCC

Abstract Hepatocellular carcinoma (HCC) is a highly invasive malignant tumor. Tumor‐associated fibroblasts (CAFs) and tumor‐associated macrophages (TAMs) play important roles in the invasive process and immune escape of HCC. To overcome these barriers, this work has designed a biomimetic dual‐engine nanodisruptor (ZHL@CM) by encapsulating losartan (LST) and Radix Hedysari polysaccharide (HPS) within a zeolitic imidazolate framework (ZIF) and camouflaging the construct with macrophage membranes. In the acidic tumor microenvironment, ZHL@CM rapidly releases LST, which penetrates the dense ECM and reprograms CAFs to suppress collagen synthesis at the source. Simultaneously, Zn ²⁺ released from ZIF directly degrades peritumoral ECM components, collectively alleviating matrix stiffness and dismantling the physical barrier. These effects facilitate the deep penetration of macromolecular agents and immune effector cells into tumor tissues. The liberated HPS efficiently infiltrates the tumor parenchyma and reprograms TAM2 toward a proinflammatory phenotype by activating the TLR4 signaling cascade. Beyond local remodeling, ZHL@CM elicits robust systemic immune activation, markedly suppressing metastatic dissemination. This work offers a mechanistically informed strategy for synergistic immunomodulation in HCC, providing a versatile platform for overcoming stromal and immune resistance in solid tumors.