A “Glue” Strategy to Engineer Cancer Cell Membrane‐Camouflaged Prodrug Nanoassemblies for Efficient Targeted Chemotherapy

Abstract Homodimeric prodrug nanoassemblies (HDPNs) offer a unique approach to improving the selectivity of chemo‐drugs but demonstrate suboptimal tumor targeting efficiency. Cell membrane‐camouflaged nanoparticles, particularly those using homologous cancer cell membranes (CM), can achieve excellent tumor accumulation. However, it is challenging to prepare CM‐camouflaged HDPNs due to the poor affinity between hydrophobic HDPNs and hydrophilic CM. In addition, it is unclear whether the amount of CM would affect the performance of HDPNs. Herein, the amphiphilic molecule DSPE‐PEG_2k is utilized as a “glue” to enhance the affinity between redox‐responsive paclitaxel (PTX) HDPNs and CM. The addition of 20% DSPE‐PEG_2k is found to effectively improve this affinity. Stable CM‐HDPNs are successfully prepared by fine‐tuning CM amount to a drug‐to‐membrane weight ratio of 1:0.25. Benefiting from the homologous targeting, CM‐HDPNs demonstrated high tumor accumulation followed by rapid internalization by tumor cells. In response to the redox tumor microenvironment, PTX is rapidly released, exerting efficient antitumor effects without obvious toxic effects. The “glue” strategy will provide new insights for the preparation of CM‐camouflaged nano‐formulations in the case of target‐selective chemotherapy.