Surface Hydrophobicity Dictates Environment‐dependent Colloidal Stability of Organic Phototheranostic Nanoparticles

ABSTRACT Organic phototheranostic nanoparticles (OPNPs) have gained significant attention in bioimaging, sensing, and therapy owing to their tunable optical properties and multifunctional theranostic capabilities. Composed of amphiphilic polymeric carriers (APCs) and hydrophobic chromophores, their colloidal stability in aqueous environments is critical for preserving optical performance and ensuring in vivo efficacy. Herein, we systematically compare the colloidal stability of OPNPs in physiological saline versus the bloodstream, uncovering distinct environment‐dependent behaviors that are primarily governed by OPNP surface hydrophobicity, which is tunable via the intrinsic hydrophobicity of the APCs. Specifically, OPNPs prepared with higher hydrophobic carriers aggregate in saline but remain stable in the bloodstream, whereas those with less hydrophobic carriers show the opposite trend. Mechanistically, this environment‐dependent stability arises from differential interfacial interactions: surface hydrophobicity modulates ion‐induced poly(ethylene glycol) dehydration and aggregation in saline, while governing protein‐mediated stability regulation in serum. Overall, our findings establish surface hydrophobicity as a pivotal regulator of OPNP colloidal stability and provide a rational design principle for engineering OPNPs tailored to specific biomedical scenarios (e.g., in vitro detection vs. in vivo therapy).