A synergistic nanozyme platform breaking the neuroinflammatory-oxidative stress cycle for extended pain relief.

Chronic pain represents a major public health burden that significantly compromises patient quality of life. Its persistence is driven by a vicious cycle of neuroinflammation and oxidative stress within the nervous system. Effective clinical management critically requires targeted therapeutics with long-lasting efficacy. Herein, we report a novel liposome-based co-delivery system (SeCQDs@Liposome-RA, SLR) encapsulating selenium-doped carbon quantum dots (SeCQDs) nanozymes and the potent anti-inflammatory agent Raddeanin A (RA). This platform was rationally engineered for synergistic antioxidant and anti-inflammatory actions. In vitro, SLR nanoparticles efficiently neutralized reactive nitrogen and oxygen species and significantly suppressed pro-inflammatory cytokines in activated microglia. Crucially, leveraging the liposome's sustained-release capabilities, a single dose of SLR provided profound and durable analgesia in a Complete Freund's Adjuvant-induced inflammatory pain mouse model, lasting up to 72 h. Mechanistically, SLR disrupted the neuroinflammatory cycle by inhibiting the mitogen-activated protein kinase/nuclear factor kappa B signaling pathways, thereby suppressing microglial overactivation and mitigating oxidative stress within the spinal cord and brain. Furthermore, SLR demonstrated broad-spectrum efficacy in chemotherapy- and spared nerve injury-induced neuropathic pain models. Given its exceptional biosafety and sustained-release characteristics, SLR represents a versatile and clinically promising nanoplatform for the long-term management of chronic pain syndromes.