Matrix Metalloproteinase-2-Responsive Surface-Changeable Liposomes Decorated by Multifunctional Peptides to Overcome the Drug Resistance of Triple-Negative Breast Cancer through Enhanced Targeting and Penetrability

Although nanomedicine has demonstrated great potential for combating drug resistance, its suboptimal recognition of malignant cells and limited transport across multiple biological obstacles seriously impede the efficacious accumulation of drugs in tumor lesions, which strikingly limits its application in the clinical therapy of drug-resistant triple-negative breast cancer (TNBC). Hence, a surface-variable drug delivery vehicle based on the modification of liposomes with a multifunctional peptide (named EMC) was fabricated in this work and used for encapsulating doxorubicin and the p-glycoprotein inhibitor tariquidar. This EMC peptide contains an EGFR-targeting bullet that was screened from a “one-bead one-compound” combinatorial library, an MMP-2-cleaved substrate, and a cell-penetrating segment. The EGFR-targeting sequence has been validated to possess excellent specificity and affinity for EGFR at both the cellular and molecular levels and could be unloaded from the EMC peptide by MMP-2 in the tumor microenvironment. This doxorubicin/tariquidar-coloaded and peptide-functionalized liposome (DT-pLip) exhibited superior efficacy in tumor growth inhibition to drug-resistant TNBC both in vitro and in vivo through EGFR targeting, osmotic enhancement in response to MMP-2, controllable release, and inhibited efflux. Consequently, our systematic studies indicated the potential of this liposome-based nanoplatform in the therapy of drug-resistant TNBC through targeting effects and tumor microenvironment-triggered penetration enhancement.