Transformable nano-antibiotics for mechanotherapy and immune activation against drug-resistant Gram-negative bacteria

Abstract

The dearth of antibiotic candidates against Gram-negative bacteria and the rise of antibiotic resistance create a global health concern. The challenge lies in the unique Gram-negative bacterial outer membrane that provides the impermeable barrier for antibiotics and sequesters antigen presentation. We designed a transformable nano-antibiotics (TNA) that can transform from nontoxic nanoparticles to bactericidal nanofibrils with reasonable rigidity (Young’s modulus, 21.6 ± 5.9 MPa) after targeting β-barrel assembly machine A (BamA) and lipid polysaccharides (LPSs) of Gram-negative bacteria. After morphological transformation, the TNA can penetrate and damage the bacterial envelope, disrupt electron transport and multiple conserved biosynthetic and metabolic pathways, burst bacterial antigen release from the outer membrane, and subsequently activate the innate and adaptive immunity. TNA kills Gram-negative bacteria in vitro and in vivo with undetectable resistance through multiple bactericidal modes of action. TNA treatment–induced vaccination results in rapid and long-lasting immune responses, protecting against lethal reinfections.