Integrating both targeted delivery and stimulus-responsive release into a single small molecule for drug delivery presents challenges related to synthesis, stability, and efficacy. In this study, single-molecular lipids incorporating a Lewis pair (Lp-lipids) are described, composed of a Lewis acid (phenylboronic acid) and a Lewis base (amine) within a single small molecular structure, to formulate lipid nanoparticles for antibiotic delivery. For targeted delivery to bacterial biofilms, the phenylboronic acid selectively binds to bacteria or biofilms by forming boronate ester bonds with diols in the microbial dextran or peptidoglycan. Additionally, the amine group responds to the acidic microenvironment, enhancing electrostatic interactions with bacteria and biofilms. Regarding stimulus-responsive drug release, the Lewis base reacts to low pH, while the Lewis acid responds to H2O2 and ATP, triggering changes in the hydrophobicity and structural integrity of the lipid nanoparticles. These changes facilitate the release of encapsulated antibiotics, effectively eradicating both Gram-positive and Gram-negative bacteria in vitro and in vivo. The combined targeting and stimuli-responsive release properties of Lp-lipids significantly enhance their potential for biomedical applications and clinical translation.© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.