Laser-programmable glycosaminoglycan-based nanocarriers co-deliver hypocrellin B and doxorubicin for spatiotemporal chemo-photothermal therapy of hepatocellular carcinoma

CS-DHB NPs enabled pH-/laser-triggered DOX and HB codelivery for spatiotemporal HCC chemo-photothermal therapy. • Under 660 nm laser (1.0 W cm⁻²), NPs exhibited rapid hyperthermia, high ¹O₂ yield, and superior photostability. • In Hepa1-6 tumor models, NPs plus laser ensured 100% survival, marked tumor regression, and no notable toxicity. Hepatocellular carcinoma (HCC) remains lethal due to systemic chemotherapy is halted by cardiotoxicity, multidrug resistance, and poor tumor penetration. To address these limitations, we developed a novel modified chondroitin sulfate/cystamine nanoparticle, termed CS-DHB NPs, that co-delivers doxorubicin (DOX) and the photosensitizer hypocrellin B (HB) and is encapsulated within a chondroitin sulfate/cystamine nanocarrier. These engineered nanoparticles (∼154 nm) demonstrated high drug-loading efficiencies (DOX: 80%; HB: 60%), exceptional serum stability (>72 h), and dual-drug release in laser- and pH-dependent environments. Upon 660 nm laser irradiation (1.0 W cm⁻²), the CS-DHB NPs produced substantial photothermal, photodynamic effects (¹O₂ quantum yield: 0.56), and excellent photostability. The prepared CS-DHB NPs were biocompatible and showed efficient in vitro cytotoxic effects via CCK-8 assays and deep penetration and inhibition of multicellular tumor spheroids (MTS). Ex vivo cellular studies revealed that the targeted delivery mechanism, clathrin-dependent endocytosis, with laser-triggered uptake, enhanced intracellular DOX accumulation twofold. In Hepa1–6 cells, CS-DHB NPs treatment induced pronounced apoptosis (∼51%). In vivo, five intravenous administrations combined with localized laser irradiation resulted in significant tumor regression, 100% survival, minimal systemic toxicity, and no histopathological damage in a Hepa1–6-bearing C57BL/6 mice model. By integrating chemotherapy, phototherapy, and targeted release within a tumor-targeted nanosystem, CS-DHB NPs offer a promising strategy to overcome chemoresistance while preserving healthy tissues, advancing an effective, and clinically translatable approach for synergistic HCC therapy.