摘要Objective:This study aims to develop a drug controlled-release sys-tem based on nano-hydrogel technology for stone dissolution and evaluate its dual effi-cacy in synchronously dissolving calcium oxalate stones and inhibiting uropathogenic Escherichia coli.Methods:A pH-responsive chitosan(CS)-sodium alginate(SA)-hy-drogel microsphere loaded with potassium sodium hydrogen citrate and fosfomycin(CS/SA@PSHC@CS@F)was constructed using ionic cross-linking.In vitro stone dis-solution experiments were conducted to determine drug release kinetics and stone mass reduction rate under different pH environments,and the antibacterial activity a-gainst E.coli ATCC 25922 was evaluated using the plate counting method.A rat mod-el of kidney stone combined with infection was established.Stone volume changes were quantified via micro-CT,urinary interleukin-6(IL-6)and tumor necrosis factor α(TNF-α)levels were measured by ELISA,and renal tissue inflammation was scored via histopathological evaluation.Results:The 24-hour cumulative release rate of CS/SA@PSHC@CS@F at pH 5.8 reached 92.3%±4.1%,significantly higher than at pH 7.4(31.2%±3.7%,P<0.01).At 72 h,the mass reduction rate of calcium oxalate stones in CS/SA@PSHC@CS@F was 68.9%±5.2%,significantly higher than that of the PSHC+F mixture(P<0.01).Antibacterial experiments confirmed that the inhibition rate of biofilm colonies by CS/SA@PSHC@CS@F could reach 82.4%±6.7%,compared to 58.2%±5.3%for F,with a statistically significant difference(P<0.01).Animal experiments showed that the stone volume reduction rate in the CS/SA@PSHC@CS@F group was 62.3%±8.1%,higher than that in the PSHC+F group,and the decrease in urinary IL-6 level after administration was more significant,while there was no significant differ-ence in TNF-α level compared with the other two groups(P>0.05).The renal tissue inflammation score decreased to 2(1,2)points,showing a significant reduction com-pared with the other two groups(P<0.05).Conclusion:The novel controlled-release system designed in this study achieves targeted drug release in the stone infection mi-croenvironment through the ion exchange mechanism,simultaneously enhancing stone dissolution efficiency and antibacterial effect,thereby providing a new drug delivery strategy for the treatment of urinary stones combined with infection.