Quasi-opsonin conjugated lipase-sensitive micelles activate macrophages against facultative intracellular bacterial infection.
Xinyue LiuYajie WangJiahui ZouHui WangXuechun LiYing HuangEnshi HuZhiyu GuanDanyi QuanJianping LiuWenli ZhangPublished in: Journal of materials chemistry. B (2023)
Drug resistance caused by facultative intracellular bacteria such as Salmonella typhimurium ( S. typhimurium ) is still a tough challenge. Bacteria phagocytosed by macrophages have evolved a variety of mechanisms to defend against host attack, and the poor entry of antibiotics into infected macrophages is conducive to the survival of intracellular bacteria. In this report, we prepared a quasi-opsonized chloramphenicol (Chl)-loaded micellar system (B-mLBP-M/Chl) assembled by a bacterial lipase-sensitive polymer with a conjugate of lipopolysaccharide-binding protein (LBP) analog and biotin (B) as a ligand, which could eliminate drug-resistant S. typhimurium with quasi-opsonization via 3 steps: (i) target and release antibiotics on bacteria lipase, (ii) opsonize S. typhimurium to be digested by the macrophage, and (iii) activate the macrophage for fighting. The B-mLBP-M/Chl could target bacterial LPS through mLBP by simulating the N-terminal sequence of native LBP, exhibiting a high ability to target the localized infection site in mice. It could also activate the phagocytosis of macrophages via coupled biotin, cooperating with antibiotics and effectively improving the survival of mice with little pathological damage to tissues. Moreover, compared with native opsonin, B-mLBP does not cause an excessive inflammatory response and could recover homeostasis after exerting the quasi-opsonization by regulating the levels of pro-inflammatory cytokines and anti-inflammatory cytokines. With a universal target site for Gram-negative bacteria and macrophage activation, this B-mLBP-M/Chl could be applied to other bacterial infections in the future. In particular, this analog may also serve as a useful template to design safe artificial opsonin, which could be a ligand for drug delivery systems or prodrugs.
Keyphrases
- hyaluronic acid
- inflammatory response
- drug resistant
- listeria monocytogenes
- adipose tissue
- multidrug resistant
- binding protein
- solid state
- acinetobacter baumannii
- reactive oxygen species
- escherichia coli
- lipopolysaccharide induced
- toll like receptor
- lps induced
- drug delivery
- gene expression
- cancer therapy
- anti inflammatory
- oxidative stress
- high fat diet induced
- metabolic syndrome
- type diabetes
- wound healing
- current status
- free survival
- amino acid