Camouflaged Hybrid Cancer Cell‐Platelet Fusion Membrane Nanovesicles Deliver Therapeutic MicroRNAs to Presensitize Triple‐Negative Breast Cancer to Doxorubicin

Abstract Camouflaged cell‐membrane‐based nanoparticles have gained increasing attention owing to their improved biocompatibility and immunomodulatory properties. Using nanoparticles prepared from the membranes of specific cell types or fusions derived from different cells membranes, their functional performance could be improved in several aspects. Here, cell membranes extracted from breast cancer cells and platelets are used to fabricate a hybrid‐membrane vesicle (cancer cell‐platelet‐fusion‐membrane vesicle, CPMV) loaded with therapeutic microRNAs (miRNAs) for the treatment of triple‐negative breast cancer (TNBC). A clinically scalable microfluidic platform is presented for fusion of cell membranes. The reconstitution process during synthesis allows for efficient loading of miRNAs into CPMVs. Conditions for preparation of miRNA‐loaded CPMVs are systematically optimized and their property of homing to source cells is demonstrated using in vitro experiments and therapeutic evaluation in vivo. In vitro, the CPMVs exhibit significant recognition of their source cells and avoided engulfment by macrophages. After systemic delivery in mice, CPMVs show a prolonged circulation time and site‐specific accumulation at implanted TNBC‐xenografts. The delivered antimiRNAs are sensitized TNBCs to doxorubicin, resulting in an improved therapeutic response and survival rate. This strategy has considerable potential for clinical translation to improve personalized therapy for breast cancer and other malignancies.