Polymyxin B (PMB) is highly effective against Gram-negative bacterial infections, notably in targeting lipopolysaccharide (LPS), making it a vital last-resort treatment for carbapenem-resistant Klebsiella pneumoniae (CRKP) infections. However, its clinical application is hampered by nephrotoxicity and complications arising from its positive charge. This study introduces dendritic mesoporous organosilica nanoparticles loaded with PMB (PBSi-NPs), designed to overcome these limitations. The PBSi-NPs, with an average size of 170 nm, demonstrate effective LPS scavenging, enhanced bacterial internalization, and potent bactericidal properties. Their ability to release PMB in acidic microenvironments, characteristic of bacterial infections, significantly enhances the management of severe CRKP-induced infections. Notably, PBSi-NPs exhibit reduced toxicity towards human embryonic kidney cells (HEK 293), attributed to their stimulus-responsive design. In vivo, they exhibit higher targeting of lung cells than free PMB, specifically alveolar and bronchial cells, and effectively treat severe pneumonia in a CRKP (isolated from clinical sample) induced mouse model, markedly improving survival rates. This study proposes a novel, cost-effective method for PMB delivery using PBSi-NPs, potentially broadening the scope of nanomedicine for treating critically ill CRKP-infected patients.