Carboxymethyl chitosan/sodium alginate-based dynamic organic nanocomposite hydrogel for local tumoral targeted...

The nanocomposite hydrogels fail to achieve clinical transformation due to their unsatisfactory nanomedicine escapement from hydrogel and suboptimal tumor selectivity. Herein, this work highlights a successful development of a polysaccharide-based dynamic organic nanocomposite hydrogel, in which crosslinked nano-prodrugs (NPs) are dispersed within liquid hydrophobic orthoester (OE) and subsequently encapsulated in polysaccharide-based hydrogels crosslinked via dynamic imine bonds. These dynamic imine linkages endow the hydrogel with injectability, self-adaptability, and tumor extracellular pH-responsive biodegradability. OE enables efficient NPs release from the hydrogel, enhances their deep penetration into tumor tissues, and undergoes further degradation to restore NPs to their original particle size. The NPs enhance selective drug accumulation through tumoral intracellular pH-triggered aggregation and enable targeted drug release in response to specific intracellular pH/glutathione conditions, ultimately promoting apoptosis and cytotoxicity through a synergistic interaction between cisplatin and demethylcantharidin. These superior attributes allow for complete tumor suppression without adverse effects. Consequently, this polysaccharide-based dynamic organic nanocomposite hydrogel demonstrates substantial potential for localized tumor-targeted therapy, greatly improving its clinical applicability.