Enzyme‐Responsive Polyion Complex Nanoparticles of Cationic Antimicrobials for Activatable Antibacterial Therapy

Abstract A self‐assembled “caging” strategy is presented for the safe delivery of potent cationic antimicrobials that suffer from non‐specific toxicity for the effective treatment of in vivo systemic bacterial infection. The key development here is a new block copolymer consisting of a poly(ethylene glycol) (PEG) stealth block and an anionic and lipase‐degradable block of poly(ɛ‐caprolactone) (PCL) and phosphonic acid‐bearing methacrylate copolymer, synthesized by hybrid copolymerization of methacrylate and cyclic esters. The anionic blocks electrostatically interact with cationic antimicrobials to form neutrally charged polyion complexes with the PEG blocks on the surface. The PCL component imparts the nanocomplex with biodegradability by bacterial secretory lipase. In the proof‐of‐concept study, cationic polyimidazolium that shows excellent antibacterial activity but severe toxicity is packaged by the block copolymer into nanocomplexes, which are stable in complex environments of high salt and protein concentrations and released the antimicrobials upon degradation of the copolymer by bacteria‐secreted lipase. The “caging” formulation of polyimidazolium eliminated its toxicity and led to highly effective bactericidal performance comparable to free polyimidazolium. This caging strategy does not require sophisticated chemical modification of cationic antimicrobials, offering a broadly applicable formulation strategy to overcome their common toxicity issue that has become a primary translational barrier.