pH-Ultrasensitive Polyester Nanoprobe for High-Contrast Tumor Imaging with Superior Biocompatibility

Transistor-like nanoprobes enable highly sensitive detection of dysregulated pH, showing great promise for tumor imaging. Their pH sensitivity arises from protonation of ionizable tertiary amines on the polymer side chains, which can increase the interaction with negatively charged cell membranes, raising risks of cytotoxicity and biosafety. Herein, we present a platform of pH-ultrasensitive polyester nanoprobes (pUPNs) that exhibit minimal toxicity upon activation and feature tunable pH responsiveness. The pUPNs self-assemble from pH-responsive polyesters, whose backbones possess high steric hindrance to minimize interactions with cell membranes. Their side chains are covalently grafted with ionizable tertiary amines and self-quenched fluorescent dyes to finely adjust the sensitivity to subtle pH variations. Interestingly, pUPN with the lowest transition pH exhibits the best tumor imaging contrast. These pUPNs demonstrated excellent biocompatibility after intravenous administration with no detectable hepatic or renal toxicity. This study presents a design platform for pH-ultrasensitive nanoprobes with excellent sensitivity and biocompatibility through increased steric hindrance in the polymer backbone.