An engineered nanoplatform cascade to relieve extracellular acidity and enhance resistance-free chemotherapy.

Tumor extracellular acidity and chemoresistance are regarded as the main obstacles to achieving optimal chemotherapeutic efficacy in tumor therapy. Herein, a new kind of acid-cascade P-S-Z nanoparticles (NPs) is developed to relieve extracellular acidosis and enhance chemotherapy without causing drug resistance. The P-S-Z NPs selectively accumulate in tumors and then regulate the release of S-Z NPs containing syrosingopine (Syr) and acid-activated prodrug ZMC1-Pt depending on the extracellular acidity. Benefiting from their small size and positive surface charge, S-Z NPs are easily internalized by tumor cells in deep tumor tissue, facilitating the release of Syr to inhibit lactic acid excretion and ultimately enhance cell acidosis. The prolonged intracellular acidosis not only inhibits tumor cell proliferation, but also continuously triggers the activation of ZMC1-Pt prodrug, a platinum-based chemotherapeutic drug that effectively eliminates cancer cells and restores wild-type p53 function to prevent tumor chemoresistance. As a proof of concept, this is a promising strategy to transfer the adverse effect of intracellular acidosis to facilitate chemotherapy. This well-designed delivery system effectively kills tumor cells without causing significant tumor drug resistance, thus opening a new window to treat cancer.