Core–Shell Type Nanoagent Enables Phototriggered Synergistic Antitumor Activity via Chlorine Radical-Induced and Nitric Oxide-Enhanced Oxidative Damage

Chlorine radical (•Cl) has shown great promise as an active species for enhancing oxidative stress in antitumor therapy. Herein, a core-shell type of nanoagent (<i>m</i>SU@A-NPs@F-R) capable of destroying cancer cells via the synergistic effect between two photogenerated active species, chlorine radical (•Cl) and nitric oxide (NO), was developed with the crucial involvement of upconversion nanoparticles (UCNPs), AgCl nanoparticles, and l-arginine. The <i>m</i>SU@A-NPs@F-R is photoactivated through the ability of UCNPs to upconver near-infrared (NIR) light into ultraviolet (UV) light, which subsequently mediates the generation of •Cl and Ag atoms. Additionally, Ag atoms mediate the release of NO from l-arginine, while NO promotes the generation of •Cl by acidifying the microenvironment. It is expected that the •Cl species induces oxidative damage to vital cellular components, including DNA backbone and mitochondrial membrane, while NO stabilizes oxidative damage of DNA and exacerbates mitochondrial injury. The high-performance therapeutic efficacy of <i>m</i>SU@A-NPs@F-R nanoagents, based on the aforementioned •Cl-induced oxidative damage to nuclear DNA and mitochondria combined with the NO-based fixation effect, was unequivocally demonstrated in tumor cell lines <i>in vitro</i> and cell-derived tumor xenograft (CDX) models <i>in vivo</i>.