Tailoring pH-ultra-sensitive oncolytic polyesters via a manageable polymer blending strategy

pH-Ultra-sensitive oncolytic polymers hold great promise for cancer therapy due to their selective oncolytic activity in the tumor microenvironment. However, achieving well-defined structures and finely tunable pH responsiveness for these polymers remains a challenge. Herein, we developed a straightforward blending strategy using two well-defined alternating polyesters with distinct pH sensitivities to create pH-ultra-sensitive hybrid polyester nanoparticles (Hps) with precisely engineered responsiveness. By varying the mass ratio of the two components, the pKa of the Hps could be continuously tuned from 6.37 to 7.01. The resulting Hps demonstrated a sharp pH-dependent membranolytic activity switch within a 0.3 pH unit window, with minimal cytotoxicity observed at pH values above the transition pH. A lead Hp formulation identified through screening exhibited potent cytotoxicity at pH 6.8, along with a favorable safety profile and significant antitumor efficacy in vivo. This blending strategy establishes a flexible and simple platform for customizing pH responsiveness of oncolytic polymers, advancing oncolytic therapy.