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 p<em>K</em>_a 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 <em>in vivo</em>. This blending strategy establishes a flexible and simple platform for customizing pH responsiveness of oncolytic polymers, advancing oncolytic therapy.