Refractory wounds in diabetic foot heal slowly. Lycium barbarum polysaccharides has been found to have the effect of lowering blood sugar. At the same time, the role of CXCL12/CXCR4 signaling in the healing process of diabetic foot has attracted much more attention. This study aimed to explore the mechanism by which Lycium barbarum polysaccharide liposome nanoparticles improve slow healing of refractory wounds in diabetic feet through CXCL12/CXCR4 signaling axis. A rat model of diabetic foot trauma was constructed and lipid nanoparticles-Lycium barbarum polysaccharides (LNP-LBP) nanocomposite was prepared and administrated into the rats. During the administration process, wound healing conditions were observed and recorded. HE staining was performed on each group, and inflammatory factors, CXCR4, and podocyte marker protein Nephrin were observed. Compared with control group, the blood sugar levels and inflammatory factor IL-6 levels of mice in the Lycium barbarum polysaccharide liposome nanoparticles group were reduced, and the wound healing speed was significantly accelerated (P < 0.05). LNP-LBP significantly reduced the levels of CXCL12 and CXCR4 in mouse wound tissues (P < 0.05). Moreover, when LNP-LBP and CXCL12/CXCR4 signaling axis inhibitors were used in combination, the wound healing speed was further accelerated and IL-6 levels were significantly increased. LNP-LBP can reduce the blood sugar level of diabetic foot rats, reduce the inflammatory response of diabetic foot wounds and swelling of wound podocytes, promote cell autophagy to speed up metabolism, thereby promoting refractory wounds healing in diabetic foot. The effect is related to inhibiting the expression of CXCL12/CXCR4 signaling.