Programmed Multiresponsive Vesicles for Enhanced Tumor Penetration and Combination Therapy of Triple‐Negative Breast Cancer

Nanomedicine is a promising approach for combination chemotherapy of triple-negative breast cancer (TNBC). However, the therapeutic efficacy of nanoparticulate drugs is suppressed by a series of biological barriers. The authors herein present a programmed stimuli-responsive liposomal vesicle to overcome the sequential barriers for enhanced TNBC therapy. The intelligent vesicles are engineered by integrating an enzyme-cleavable polyethylene glycol (PEG) corona, a light-responsive photosensitizer pheophorbide a (PPa), and a temperature-sensitive liposome (TSL) into a single nanoplatform. The resultant enzyme, light, and temperature multisensitive liposome (ELTSL) is sequentially coloaded with a lipophilic oxaliplatin prodrug of hexadecyl-oxaliplatin carboxylic acid (HOC) and hydrophilic doxorubicin hydrochloride (DOX). Dual drug-loaded ELTSL displays enhanced tumor penetration and increased cellular uptake upon matrix metalloproteinase 2 mediated cleavage of the PEG corona. Under NIR laser irradiation, PPa induces mild hyperthermia effect to trigger ultrafast drug release in the tumor cells. In combination with PPa-mediated photodynamic therapy, HOC and DOX coloaded ELTSL show significantly improved antitumor efficacy than monotherapy. Given the clinically translatable potential of the liposomal vesicles, ELTSL might represent a promising nanoplatform for combination TNBC therapy.