An injectable selenite-containing hydrogel for synergistic tumor therapy by triggering ROS/RNS generation and disrupting NADPH homeostasis

The anti-cancer effect of selenite (SeO32- ) is limited by its short half-life and narrow therapeutic window. Peroxynitrite (ONOO-), the most active reactive nitrogen species (RNS) derived from nitric oxide (NO) reacting with superoxide anion (O2 center dot- ), is still not fully exploited in the combination therapy against cancers. Herein, an injectable hydrogel is developed to trigger intracellular reactive oxygen species (ROS)/RNS bursts and disrupt nicotinamide adenine dinucleotide phosphate (NADPH) homeostasis via an innovative SeO32- -based strategy. Calcium selenite/L-Arginine (L-Arg) nanospheres (SL NPs) are synthesized as the donor of NO and SeO32- . The injectable Alg@SLGA sol composed of SL NPs, glucose oxidase (GOx), 6-aminonicotinamide (6-AN, an inhibitor of the pentose phosphate pathway (PPP)), and sodium alginate (Alg) can convert to gel in a physiological environment. Peritumoral injection of Alg@SLGA hydrogel is performed for safe and targeted treatment. The loaded GOx catalyzes glucose oxidation to produce acidic H2O2, initiating the release of NO and SeO32- from Alg@SLGA. SeO32- reacts with intracellular GSH and H2O2 to generate center dot OH and O2 center dot- , which further interacts with NO to form ONOO-. The SeO32- and 6-AN synergistically trigger intracellular NADPH exhaustion by promoting cystine metabolism-mediated NADPH consumption and inhibiting NADPH generation, respectively. Moreover, Alg@SLGA effectively induces immunogenic cell death (ICD) of tumor cells, further provoking systemic antitumor immune responses. As a consequence, the injectable Alg@SLGA hydrogel achieves enhanced ROS/RNSmediated combination therapy by synergistically disrupting NADPH homeostasis and improving antitumor immunity.