随着细菌耐药性的快速出现和广泛传播，导致抗菌药物对致命性细菌病原体的疗效逐渐降低。目前新型抗菌药物的发现和开发进展十分缓慢，因此迫切需要新的治疗策略来对抗多重耐药（multidrug-resistant, MDR）细菌，尤其是宿主细胞中的病原菌。功能性纳米颗粒作为细胞内药物递送系统具有良好发展潜力，主要优点为高生物相容性和可调节的表面修饰。基于纳米颗粒刚性可增强细胞摄取，制备了涂有细菌响应性磷脂的刚性功能化纳米颗粒（rigidity-functionalized nanoparticles, RFN）以促进内吞作用，从而增加细胞内抗菌药物累积。以耐甲氧西林金黄色葡萄球菌（methicillin-resistant Staphylococcus aureus, MRSA）和致病性蜡样芽孢杆菌为模型，RFN在4 h 内清除了99%的MDR细菌，证明了其精准递送和高抗菌疗效。另外，通过改变表面的磷脂成分来调节静电效应，实现了RFN精准靶向溶酶体和重新编程其在细胞内分布。最后，RFN在由MRSA引起的伤口感染和菌血症动物模型中显示出高疗效。综上所述，本研究提供了一个易于调控的刚性递送系统，该系统具有响应释放特性，并且通过抗菌药物胞内重分布提升抗菌疗效，为未来针对胞质细菌感染的精准治疗提供新思路。

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 development 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 aureus (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 lysosomes. 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.