Osteoarthritis(OA),a debilitating joint disorder affecting millions worldwide,is characterized by persistent inflammation,oxidative stress,and irreversible cartilage breakdown,yet remains without diseasemodifying ther...Osteoarthritis(OA),a debilitating joint disorder affecting millions worldwide,is characterized by persistent inflammation,oxidative stress,and irreversible cartilage breakdown,yet remains without diseasemodifying therapies.Inspired by natural enzymatic cascades,we developed a bioinspired nanocomposite hydrogel,N,S-doped Mn-Nb(C-CeO),that mimics endogenous antioxidant pathways to reprogram the OA microenvironment.This system combines N,Sdoped Mn-Nb_(2)C MXene nanosheets with CeO_(2)nanozymes within a boronate ester-crosslinked hydrogel,forming an“immuno-redox circuitry”with four synergistic functions:(1)cascade reactive oxygen species(ROS)scavenging via superoxide dismutase-like Mn-Nb_(2)C and catalase-like CeO_(2),amplified by photothermal enhancement under near-infrared irradiation;(2)broad reactive nitrogen species clearance,removing peroxynitrite(ONOO^(-)),nitric oxide(NO),and nitroxyl(NO^(-))to mitigate inflammation;(3)immunomodulation through Mn^(2+)-activated cGAS-STING signaling,which promoted macrophage polarization toward the M2 phenotype,concomitantly reducing the levels of pro-inflammatory cytokines such as interleukin-1 beta(IL-1β)and tumor necrosis factor-alpha(TNF-α);(4)cartilage regeneration via pH/ROS-responsive simvastatin(SIM)release and nanocatalysis,upregulating SRY-box transcription factor 9(SOX9)and Col2a1 while inhibiting matrix metalloproteinase-13(MMP-13)and a disintegrin and metalloproteinase with thrombospondin motifs 5(ADAMTS5).In a murine OA model,the system reduced synovitis by 60%,restored 80% of cartilage thickness,and suppressed osteophyte formation,outperforming singlecomponent treatments.This strategy pioneers a“self-healing cartilage”approach by integrating nanocatalysis with immunoengineering for transformative OA therapy.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82101647 and 82203446)Natural Science Fund of Zhejiang Province(Nos.LY24H250001,LQN25H060003,and LY23H060011)+2 种基金the Postdoctoral Fellowship Program of CPSF(No.188020-170257701/136)the Regional Innovation and Development Joint Fund of the National Natural Science Foundation of China(No.U22A20282)the Guangdong Basic and Applied Basic Research Foundation(No.2023A1515220225).
文摘Osteoarthritis(OA),a debilitating joint disorder affecting millions worldwide,is characterized by persistent inflammation,oxidative stress,and irreversible cartilage breakdown,yet remains without diseasemodifying therapies.Inspired by natural enzymatic cascades,we developed a bioinspired nanocomposite hydrogel,N,S-doped Mn-Nb(C-CeO),that mimics endogenous antioxidant pathways to reprogram the OA microenvironment.This system combines N,Sdoped Mn-Nb_(2)C MXene nanosheets with CeO_(2)nanozymes within a boronate ester-crosslinked hydrogel,forming an“immuno-redox circuitry”with four synergistic functions:(1)cascade reactive oxygen species(ROS)scavenging via superoxide dismutase-like Mn-Nb_(2)C and catalase-like CeO_(2),amplified by photothermal enhancement under near-infrared irradiation;(2)broad reactive nitrogen species clearance,removing peroxynitrite(ONOO^(-)),nitric oxide(NO),and nitroxyl(NO^(-))to mitigate inflammation;(3)immunomodulation through Mn^(2+)-activated cGAS-STING signaling,which promoted macrophage polarization toward the M2 phenotype,concomitantly reducing the levels of pro-inflammatory cytokines such as interleukin-1 beta(IL-1β)and tumor necrosis factor-alpha(TNF-α);(4)cartilage regeneration via pH/ROS-responsive simvastatin(SIM)release and nanocatalysis,upregulating SRY-box transcription factor 9(SOX9)and Col2a1 while inhibiting matrix metalloproteinase-13(MMP-13)and a disintegrin and metalloproteinase with thrombospondin motifs 5(ADAMTS5).In a murine OA model,the system reduced synovitis by 60%,restored 80% of cartilage thickness,and suppressed osteophyte formation,outperforming singlecomponent treatments.This strategy pioneers a“self-healing cartilage”approach by integrating nanocatalysis with immunoengineering for transformative OA therapy.
