A peptide-nanoparticle conjugate to steer elimination of drug-resistance bacteria and LPS

With prevalence of bacterial resistance and decline in antibiotic development, immunotherapy is emerging as a promising strategy for bacterial infections. Macrophages play a crucial role in bacterial eradication and lipopolysaccharide (LPS) detoxification. However, overactivated macrophages triggered by excess LPS can also induce inflammatory injury and impaired antimicrobial response. Therefore, nanotherapies that synergize with and/or steer macrophages to simultaneously eliminate bacteria and LPS, provide an optimal strategy for immunomodulation to achieve a balance between antimicrobial and inflammatory responses. Inspired by antibody-drug conjugates (ADCs), we report a peptide-nanoparticle conjugate (PNC) composed of opsonized peptides (B-mBPI) and engineered nanoparticle (PEGylated liposomes loaded with antibiotic). This PNC could effectively neutralized LPS with high affinity and specifically tag bacteria, then guiding macrophages towards the elimination of bacteria and LPS. With this steering-elimination function, a synergistic interaction was observed by evaluating the combination index (CI) of PNC and macrophages towards the antibacterial effect (CI = 0.103 < 1). Besides, we found that the dual-route administration regimen combining intraperitoneal (i.p) and intravenous (i.v) delivery of PNC demonstrated superior therapeutic efficacy compared to single-route therapy in intraperitoneal infection, highlighting the importance of tailoring nanocarrier delivery to infection dynamics. Consequently, this PNC significantly reduced the bacterial burden by more than 3 orders of magnitude and effectively reduce inflammatory factors (TNF-α, IL-6) and LPS levels to baseline, leading to a substantial improvement in the survival rate of mice infected with drug-resistant Escherichia coli ( E. coli ) (0 % improved to 71.4 %). This PNC presents a paradigm for antimicrobial immunotherapy by steering elimination of bacteria and LPS as well as modulating immune response.