Promote Intratumoral Drug Release and Penetration to Counteract Docetaxel‐Induced Metastasis by Photosensitizer‐Modified Red Blood Cell Membrane‐Coated Nanoparticle

Abstract The red blood cell membrane (RBCm) provides tight protection, lowers the immunogenicity, and prolongs the circulation time of drugs in vivo when acting as the coating of drug delivery systems. However, the cellular uptake and release of drugs are hindered by RBCm. Docetaxel (DTX) is the first‐line medicine for treating triple‐negative breast cancer (TNBC), but it induces tumor metastasis. To solve these dilemmas, in this study, the photosensitizer 1,1‐dioctadecyl‐3,3,3,3‐tetramethylindotricarbocyanine iodide (DiR)‐modified RBCm (DM) is prepared, which is coated onto a hybrid micelle consisting of the prodrugs of DTX and the anti‐metastasis agent calcitriol (CTL), obtaining a nanoparticle, named HDC‐DM. In a 4T1 tumor‐bearing mouse model, after injecting HDC‐DM, the intratumoral DTX and CTL concentrations are increased by 1.7 and 2.5 times compared with the free drug groups. After irradiating tumors with near‐infrared laser, DiR elicits the photothermal effect, triggering the rupture of RBCm and drug release, promoting drug penetration in tumors, and inducing immunogenic cell death. The tumor growth inhibition rate is 77%, and the formation of lung metastases is reduced by 82%, with good biocompatibility. It is suggested that the combination of phototherapy, chemotherapy, and anti‐metastatic therapy using HDC‐DM is expected to be a powerful strategy for treating TNBC.