Bioinspired prodrug nanoassemblies with dual PEGylation and membrane-coating strategies to enhance membrane binding stability and antitumor efficacy

Dimeric prodrug nanoassemblies (DPNAs) offer great potential in improving the efficacy of chemotherapy. Previously, we developed tetrasulfide bonds as a novel response module and the obtained γ-4S-2CTX NPs demonstrated superlative self-assembly stability and enhanced anti-tumor efficacy. However, current DPNAs mainly rely on simple PEGylation for surface modification to improve blood circulation, which lacks tumor-selective functionality and limits their further application. To address these limitations, we introduced a new surface modification strategy using RM-1 tumor cell membranes (CMs) to enhance biofunctionality. The initial attempt to use CMs as a single surface modification failed because the affinity of nanocores-CMs remains a problem, which affected the stability of membrane-coated DPNAs. To address this, we used 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N [methoxy(polyethyleneglycol)-2000] (DSPE-PEG_2k) as an adhesive bridge to improve the affinity between CMs and DPNAs, resulting in a dual-modified formulation termed CM-pDPNAs. This dual modification strategy enhanced CMs binding to DPNAs, enabling precise tumor recognition and internalization, thereby improving tumor elimination efficacy. Furthermore, this approach addressed key challenges associated with current CM-coated nanoparticles (CM-NPs), including complex preparation procedures and poor drug-carrier compatibility. This work elucidates the application of CMs as surface modification modules, paving the way for the next generation of biomimetic prodrug nanoassemblies with superior stability and tumor specificity.