A Dually Nanobody‐Engineered Milk‐Derived Extracellular Vesicle Nanomedicine Targeting Tumour‐Associated Macrophages and Cancer Cells for Cancer Therapy

ABSTRACT Tumour development and progression are driven by intricate interactions among various cell types within the tumour microenvironment (TME). Targeting a single cell type often fails to eradicate cancer, highlighting the need for strategies to co‐target multiple cell types. MicroRNA‐21‐5p, highly abundant in tumour cells and tumour‐associated macrophages (TAMs), exerts strong cancer‐promoting effects. Epidermal growth factor receptor (EGFR) is overexpressed in various cancer types, and programmed death‐ligand 1 (PD‐L1) is expressed predominantly by TAMs in multiple cancers. In this study, we developed a dual‐targeted engineered milk‐derived extracellular vesicles system (7D12/KN035‐iEVs), decorated with 7D12 (an EGFR nanobody) and KN035 (a PD‐L1 nanobody), to specifically deliver miR‐21‐5p inhibitors into EGFR + and/or PD‐L1 + tumour cells and TAMs, thereby inhibiting tumour progression while reprogramming immunosuppressive TME. Notably, this dual‐targeting nanomedicine synergistically inhibits tumour growth when combined with immunotherapy and radiotherapy. In summary, this mEV‐based nanomedicine represents a promising universal strategy for cancer treatment, offering a versatile platform for targeting multiple components of the TME.