Mus musculus strain:C57BL/6 Raw sequence reads. Mus musculus strain:C57BL/6

Although antibiotics are central to the treatment of bacterial infections, their use causes significant disturbances in the gut microbiota and development of antibiotic resistance. Thus, innovative administration methods for delivering antibiotics that avoid side effects on microbiota are urgently needed. Here, we report a positive lipid-assisted polymeric vesicular nanocarrier with a glucosylated surface (Positive Glucosylated Nanoparticles, PGNPs) that facilitates targeted absorption of antibiotics in the proximal small intestine by exploiting the highly specific expression of the sodium-dependent glucose transporter 1 (SGLT1) protein. We show that PGNPs-loaded antibiotics (PGNPs-Abx) effectively eliminated Streptococcus pneumoniae infection in lung. Importantly, compared to standard administration of the same antibiotics, oral administration of PGNPs-Abx markedly decreased adverse effects on the intestinal microbiota; lowered both dysbiosis-associated metabolic syndrome and infection; and reduced the accumulation of known antibiotic resistance genes in commensal bacteria. Our study thus demonstrates a convenient administration method for targeted absorption of antibiotics that confers efficacy against cold-associated Streptococcus pneumoniae infection, while driving less dysbiosis and its associated risk of systemic diseases.