Nannan Wang, Ke Wang, Yuepeng Cao, Guoqing Su, Jinghang Qian, Jingru Shen, Jiayuan Jiang, Zian Chen, X Huang, Chengshuai Si, Jun Bao, Lei Ding, Liu Yang
The clinical efficacy of immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC) is restricted by a dense, rigid extracellular matrix (ECM) that acts as a physical barrier to immune infiltration. To address this resistance, a biomimetic nanoplatform (MDPAs) was developed, comprising Defactinib-loaded mesoporous silica nanoparticles encapsulated in PD-L1 antibody-conjugated platelet membranes. Leveraging platelet-mimetic adhesion for tumor accumulation, MDPAs were shown to inhibit the Integrin-FAK-YAP mechanotransduction axis, leading to YAP cytoplasmic sequestration and attenuated cytoskeletal tension. This alleviation of the mechanical niche is associated with enhanced cytotoxic T cell infiltration, which synergizes with co-delivered PD-L1 antibodies to activate antitumor immunity. Single-cell RNA sequencing reveals that MDPAs remodel immune-epithelial-stromal crosstalk, driving tumor cells from a mesenchymal-like phenotype toward an immunologically susceptible, antigen-presenting state. In orthotopic, liver metastasis, and post-surgical recurrence models, MDPA treatment elicited tumor regression and extended survival with a favorable biosafety profile. These findings suggest that modulating tumor mechanics may represent an effective strategy to sensitize refractory CRC to immunotherapy.