Enhanced Intracellular IR780 Delivery by Acidity-Triggered PEG-Detachable Hybrid Nanoparticles to Augment Photodynamic and Photothermal Combination Therapy for Melanoma Treatment

The PEGylation of drug-carrying nanoparticles has often been used to prolong blood circulation and improve drug deposition at tumor sites. Nevertheless, the PEG-rich hydrophilic surfaces retard the release of the payloads and internalization of therapeutic nanoparticles by cancer cells, thus lowering the anticancer efficacy. To boost the anticancer potency of the combined photodynamic therapy (PDT) and photothermal therapy (PTT) against melanoma by conquering the PEG dilemma, herein, the hybrid PEGylated chitosan-covered polydopamine (PDA) nanoparticles (PCPNs) with acidity-elicited PEG detachment ability were fabricated as carriers of IR780, a small-molecule photosensitizer used for PTT and PDT. The IR780@PCPNs displayed a uniform, solid-like spherical shape and sound colloidal stability. Under near-infrared (NIR) irradiation, the IR780@PCPNs showed prominent photothermal conversion efficiency (ca. 54.6%), robust photothermal stability, reduced IR780 photobleaching, sufficient singlet oxygen (¹O₂) production, and glutathione-depleting ability. Moreover, with the environmental pH being reduced from 7.4 to 5.0 at 37 °C, the decreased interactions between IR780 and PCPNs due to the increased protonation of phenolic hydroxyl residues within PDA and primary amine groups of chitosan accelerated the release of IR780 species from IR780@PCPNs. Importantly, the cellular uptake of IR780@PCPNs by B16F10 melanoma was remarkably promoted in a weakly acidic milieu upon PEG detachment driven by the disintegration of acid-labile benzoic imine. With NIR irradiation, the internalized IR780@PCPNs generated hyperthermia and ¹O₂ to damage mitochondria, thereby effectively inhibiting the proliferation of B16F10 cells. Collectively, our findings present a practical strategy for amplifying the anticancer efficacy of PTT combined with PDT using PEG-detachable IR780@PCPNs.