Inhalable upper critical solution temperature-type polymer nanoparticles with gradient spatial protonation and...

Inhalable nanodelivery faces a tricky and paradoxical interfacial challenge: penetrating mucus requires nanoparticles to be negatively charged or neutral to avoid electrostatic trapping, whereas targeting and disrupting bacterial biofilms strongly relies on positive charges. To address this, we developed inhalable polymer nanoparticles featuring gradient spatial protonation and thermal expansion to overcome mucus and biofilm barriers. Herein, poly(acrylamide-co-acrylonitrile) (P(AAm-co-AN)) with upper critical solution temperature (UCST) as thermo-responsive backbone, combined together with 2,4,5-triaminopyridine as cross-linking point, and N-(3-dimethylaminopropyl)-1,3-propanediamine as surface modifier, to impart the dual-responsive capability. They naturally exhibited thermo-responsive behavior that accelerated antibiotic release in hyperthermia inflammation site, and pH-dependent charge reversal from -13.45±0.63 (pH 7.4) to +22.51±0.31 mV (pH 5.0). This synergistic effect enabled them to overcame multiple physiological barriers through enhanced mucus penetration, improved cellular uptake, and efficient lysosomal escape. In particular, they exhibited inherent antibacterial activity in acidic inflammation microenvironment, significant biofilm penetration capability and immunomodulatory effects. This multifunctional platform not only validates the advantages of gradient spatial protonation in complex biological interfaces but also provides a physicochemical strategy for designing smart nanocarriers to overcome physiological multibarriers. STATEMENT OF SIGNIFICANCE: Inhaled nanomedicines face a paradoxical interfacial challenge: mucus traps positively charged particles, while bacterial biofilms require them for penetration. To address these contradictory requirements, we designed a polymeric nanoparticle featuring triple-level amine system. This design enabled gradient spatial protonation, driving a charge reversal from -13.45±0.63 mV at pH 7.4 to +22.51±0.31 mV at pH 5.0 within acidic infection microenvironments. Consequently, these nanocarriers achieved 83% mucus penetration under normal physiological conditions and 100% biofilm penetration in acidic infection microenvironment. Notably, the polymer network itself physically disrupted bacterial membranes and modulated macrophage polarization toward the anti-inflammatory phenotype, even without loaded antibiotics. This work is anticipated to provide a promising strategy for overcoming complex biological interfaces in inhalable nanodelivery.