Excessive uptake of purine and glucose can lead to hyperglycemia and hyperuricemia, mediated by specific intestinal transport proteins. Currently, there is a deficiency in targeted regulation of these proteins. In this study, we introduce an oral approach for targeted modulation using electrospun core–shell short-fibers that settle on the intestinal mucosa. These fibers, designed for the controlled in situ release of phlorizin—a multi-transporter inhibitor—are crafted through a refined electrospinning-homogenizing process using polylactic acid and gelatin. Phlorizin is conjugated via a phenyl borate ester bond. Furthermore, a calcium alginate shell ensures intestinal disintegration triggered by pH changes. These fibers adhere to the mucosa due to their unique structure, and phlorizin is released in situ post-ingestion through glucose-sensitive cleavage of the phenyl borate ester bond, enabling dual-target inhibition of intestinal transporter proteins. Both in vitro and in vivo studies confirm that the short-fibers possess intestine-settling and glucose-responsive properties, facilitating precise control over transport proteins. Using models of hyperuricemia and diabetes in mice, treatment with short-fibers results in reductions of 49.6% in blood uric acid and 17.8% in glucose levels, respectively. Additionally, 16S rRNA sequencing indicates an improved intestinal flora composition. In conclusion, we have developed an innovative oral strategy for the prevention of hyperglycemia and hyperuricemia.