A strategy trapping transient radicals from cold atmospheric plasma triggers disulfidptosis of cancer cells

Cold atmospheric plasma (CAP) has demonstrated unique therapeutic benefits by selectively targeting a broad spectrum of cancer cells while sparing their non-malignant counterparts. Yet, current clinical applications of CAP remain largely restricted to adjuvant use during surgery, while alternative forms such as plasma-activated medium (PAM) are limited by the predominance of longer-lived species, lacking the short-lived radicals central to CAP’s potent anticancer effects. To overcome this limitation, we developed FAE@CHG, a stable functional hydrogel capable of preserving reactive oxygen and nitrogen species for long-term. The system integrates CAP pre-treated functional nanoparticles (Fe 3 O 4 @Au@EN2, FAE) with a tyramine-conjugated hyaluronic acid hydrogel (HAT). While FAE captures short-lived radicals, HAT enables sustained release and prolongs stability. FAE@CHG preserved these highly reactive species for up to three weeks, far exceeding their natural microsecond-scale lifetimes. Using cutaneous squamous cell carcinoma as the tumor model, FAE@CHG demonstrated potent and selective anticancer response through concurrent activation of multiple regulated cell death pathways that was primarily orchestrated by disulfidptosis. Animal models confirmed FAE@CHG’s enhanced efficacy over controls, with no apparent systemic toxicity via both topical use and integrated regimen. This work presents the first successful integration of CAP-derived short-lived reactive species into a gel-based platform, offering a versatile and effective strategy to improve CAP’s anti-cancer efficacy and expand its administration routes beyond current constraints.