Extracellular Matrix‐Trapped Bioinspired Lipoprotein Prolongs Tumor Retention to Potentiate Antitumor Immunity

Abstract The immunomodulatory effects of many therapeutic agents are significantly challenged by their insufficient delivery efficiency and short retention time in tumors. Regarding the distinctively upregulated fibronectin (FN1) and tenascin C (TNC) in tumor stroma, herein a protease‐activated FN1 and/or TNC binding peptide (FTF) is designed and an extracellular matrix (ECM)‐trapped bioinspired lipoprotein (BL) (FTF‐BL‐CP) is proposed that can be preferentially captured by the TNC and/or FN1 for tumor retention, and then be responsively dissociated from the matrix to potentiate the antitumor immunity. The FTF‐BL‐CP treatment produces a 6.96‐, 9.24‐, 6.72‐, 7.32‐, and 6.73‐fold increase of CD3 + CD8 + T cells and their interferon‐γ‐, granzyme B‐, perforin‐, and Ki67‐expressing subtypes versus the negative control, thereby profoundly eliciting the antitumor immunity. In orthotopic and lung metastatic breast cancer models, FTF‐BL‐CP produces notable therapeutic benefits of retarding tumor growth, extending survivals, and inhibiting lung metastasis. Therefore, this ECM‐trapping strategy provides an encouraging possibility of prolonging tumor retention to potentiate the antitumor immunity for anticancer immunotherapy.