Tumor site-specific PEG detachment and active tumor homing of therapeutic PEGylated chitosan/folate-decorated polydopamine nanoparticles to augment antitumor efficacy of photothermal/chemo combination therapy

•Co-deposition of BI-PC adducts and DA molecules formed core–shell nanoparticles.•Hybrid nanoparticles showed prominent acid and photothermal-triggered DOX release.•Cellular uptake of hybrid nanoparticles was promoted by dePEGylation and FA exposure.•Hybrid nanoparticles largely inhibited tumor growth by photothermal/chemo therapy. To effectively promote tumor-targeted delivery of photothermal/chemo combined therapy for boosted antitumor efficacy, the versatile photothermal hybrid polymeric nanoparticles capable of detaching poly(ethylene glycol) (PEG) segments and exposing tumor-targeting folate (FA) moieties in response to tumor extracellular acidity (pHe) are developed to selectively deliver doxorubicin (DOX), a chemotherapy drug, to the tumor sites. Through one-pot co-deposition of dopamine molecules with acidity-responsive benzoic imine-containing PEGylated chitosan (BI-PC) adducts, the hybrid BI-PC/polydopamine (PDA) nanoparticles were attained as DOX vehicles and characterized to have a spherical structure composed of a PDA core surrounded by hydrophilic BI-PC shells. The DOX@BI-PC/PDA nanoparticles not only showed prominent colloidal stability in serum-containing environment and photothermal conversion efficiency, but also exhibited acidity/photothermal-activated drug release. The PEG detachment and FA exposure of FA-DOX@BI-PC/PDA nanoparticles in weak acidic environment appreciably promoted their uptake by FA receptor-overexpressed CT-26 colon cancer cells, thus largely augmenting anticancer potency based on the photothermal/chemo therapy. Importantly, the pHe-responsive FA-DOX@BI-PC/PDA nanoparticles markedly accumulated in CT-26 tumor sites in vivo and inhibited tumor growth without significant systemic toxicity upon the near infrared (NIR)-triggered hyperthermia integrated with DOX chemotherapy. This work presents a practical strategy for improved antitumor potency of photothermal/chemo combination therapy.