Dynamic polysaccharide-based organic nanocomposite hydrogel precisely mediates oral targeted therapy for colorectal cancer.

Overcoming the gastrointestinal barrier to enable precise oral drug delivery to the small intestine and colorectum is crucial for the treatment of colorectal cancer (CRC). Herein, this work highlights a dynamic polysaccharide-based organic nanocomposite hydrogel, which is successfully fabricated through incorporating lipophilic orthoester (OE)/carboxymethyl chitosan (CMCS)-based nano-prodrugs (NPs) into the gellan gum (GG) matrix. The GG can not only protect OE/NPs from gastric acid-induced degradation and ensure precise release in the small intestine and colon via pH-triggered progressive pore expansion, but also alter gut microbiota composition. OE can promote the efficient release of NPs from the hydrogel network through phase separation and subsequently restore their original particle size via its hydrolysis in the small intestine and colon. NPs can promote intestinal absorption and transport, and enhance targeted accumulation and selective synergistic cytotoxicity at CRC sites through deprotonation/protonation and dynamic size changes. Thus, the dynamic polysaccharide-based organic nanocomposite hydrogel precisely mediates oral targeted therapy for CRC, greatly advancing its application in clinics.