Antibiotic treatment failure against life-threatening bacterial pathogens is typically caused by the rapid emergence and dissemination of antibiotic resistance.The current lack of antibiotic discovery and develop-ment urgently calls for new strategies to combat multidrug-resistant(MDR)bacteria,especially those that survive in host cells.Functional nanoparticles are promising intracellular drug delivery systems whose advantages include their high biocompatibility and tunable surface modifications.Inspired by the fact that the rigidity of nanoparticles potentiates their cellular uptake,rigidity-functionalized nanoparticles(RFNs)coated with bacteria-responsive phospholipids were fabricated to boost endocytosis,resulting in the increased accumulation of intracellular antibiotics.Precise delivery and high antibacterial efficacy were demonstrated by the clearing of 99％of MDR bacteria in 4 h using methicillin-resistant Staphylococcus aur-eus(MRSA)and pathogenic Bacillus cereus as models.In addition,the subcellular distribution of the RFNs was modulated by altering the phospholipid composition on the surface,thereby adjusting the electrostatic effects and reprograming the intracellular behavior of the RFNs by causing them to accurately target lyso-somes.Finally,the RFNs showed high efficacy against MRSA-associated infections in animal models of wound healing and bacteremia.These findings provide a controllable rigidity-regulated delivery platform with responsive properties for precisely reprograming the accumulation of cytosolic antibiotics,shedding light on precision antimicrobial therapeutics against intracellular bacterial pathogens in the future.

Shaoqi Qu;Xiaoyong Huang;Xiangbin Song;Yifan Wu;Xiaowei Ma;Jianzhong Shen;Kui Zhu

National Center for Veterinary Drug Safety Evaluation,College of Veterinary Medicine,China Agricultural University,Beijing 100193,China;Guangdong Laboratory for Lingnan Modern Agriculture,Guangzhou 510642,China

工程（英文）

[1]Shaoqi Qu;Xiaoyong Huang;Xiangbin Song;Yifan Wu;Xiaowei Ma;Jianzhong Shen;Kui Zhu-.A Rigid Nanoplatform for Precise and Responsive Treatment of Intracellular Multidrug-Resistant Bacteria)[J].工程（英文）,2022(08):57-66

Nanoplatform,RFNs,aur,eus,lyso,bacteremia

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