Programmable Shrinking and Aggregation of pH-Thermo Dual-Responsive Amphiphilic Polymeric Nanoparticles Governed by Molecular Architecture

Abstract

Stimuli-responsive polymeric nanoparticles represent powerful drug delivery systems capable of responding to pathological microenvironments. However, most dual-responsive platforms are treated as binary on/off systems, and a predictive framework linking molecular architecture to nanoparticle structural evolution upon application of the stimulus is still lacking. Here, we report a modular library of amphiphilic block copolymers combining a hydrophobic polylactic acid (PLA) core-forming segment, a pH-responsive polymethacrylic acid (PMAA) stabilizing block, and a thermo-responsive poly(ethylene glycol) methyl ether methacrylate (PEGMA)-based corona, enabling programmable nanoparticle behavior across physiological pH and temperature ranges. Systematic variation of block composition and length allowed independent tuning of nanoparticle size (78-244 nm), surface charge (-53 to -4 mV), phase transition temperature (30-44 °C), and critical micelle concentration (1.55-15.82 mg L⁻¹), while preserving narrow particle size distribution and excellent colloidal stability. Importantly, the presence of PMAA segment fundamentally altered the thermo-responsive mechanism. While without PMAA the nanoparticles underwent aggregation above the phase transition temperature, with large positive size increase, PMAA-containing nanoparticles exhibited controlled and reversible intraparticle corona collapse, resulting in predictable shrinking without loss of colloidal integrity. To rationalize this behavior, we introduced a structural growth number (GN), a phenomenological descriptor capturing the balance between corona collapse, electrostatic stabilization and hydrophobic aggregation. A monotonic correlation between GN and thermo-responsive-induced size variation demonstrates that nanoparticle fate can be structurally programmed, enabling precise switching between shrinking and aggregation regimes. This modular platform establishes a predictive design strategy for dual-responsive nanocarriers and provides a foundation for engineering adaptive drug delivery systems capable of controlled size modulation and localized activation in complex biological environments.