Bacteria enmeshed in an extracellular matrix, biofilms, exhibit enhanced antibiotic tolerance. Coupled with the rapid emergence of multidrug-resistant strains, the current cohorts of antibiotics are becoming ineffective. Alternative antimicrobial approaches are therefore urgently needed to overcome recalcitrant biofilm infections. Here, we propose the use of a non-toxic lipid-polymer hybrid nanoparticle (LPN) system composed of a solid polymer core (i.e. PLGA; poly lactic-co-glycolic acid) and a cationic lipid shell (i.e. DOTAP) for localized, sustained release of antimicrobial agents to bacterial biofilms. LPNs were synthesized through a simple, robust self-assembly approach. LPNs of uniform particle size (i.e. 100-130 nm), efficiently encapsulated (up to 95%) bioimaging molecules or antibiotics and provided controlled release of the latter. The cationic lipid coating enabled the LPN to anchor onto surfaces of a diverse range of Gram-positive and Gram-negative bacterial pathogens, either in the planktonic or biofilm form. Consistently, the LPN formulations reduced more than 95% of biofilm activity at concentrations that were 8 to 32-fold lower than free antibiotics. These data clearly indicate that these novel formulations could be a useful strategy to enhance the efficacy of antimicrobials against planktonic cells and biofilms of diverse species.