Significant health risks are posed by meningitis due to its rapid progression, and challenges are encountered in intravenous antibiotic administration, especially in crossing the bloodâbrain barrier. To address this, an inflammationâactivated, endogenous macrophage (MÎŚ)âmediated oral prodrug delivery system is developed for targeted therapeutic interventions in bacterial meningitis treatment. This system is guided by inflammationâderived chemoattractants and triggers drug release through inflammationâinduced reactive oxygen species (ROS). Comprised of naturally derived βâglucans conjugated with the antibiotic cefotaxime (CTX) using a ROSâresponsive linker, nanoparticles (βGlusâCTX NPs) are formed in aqueous solutions. In a mouse model of Klebsiella pneumoniaeâinduced meningitis, orally administered βGlusâCTX NPs are traversed by intestinal microfold cells, surpassing the intestineâepithelial barrier, and are absorbed by resident endogenous MÎŚ. These MÎŚâmediated drug delivery vehicles are then traveled through the lymphatic and circulatory systems, crossing the compromised bloodâbrain barrier, ultimately reaching inflamed brain tissues, guided by their derived chemoattractants. In ROSârich inflamed tissue environments, the linkers in the βGlusâCTX NPs are cleaved, releasing therapeutic CTX for localized treatment. Targeted antibiotic treatment for bacterial meningitis is offered by this oral, endogenous MÎŚâmediated prodrug delivery system, overcoming the robust gutâtoâbrain biological barriers and potentially enhancing effectiveness for comfortable homeâbased treatment.