The emergence of multidrug-resistant (MDR) bacteria, due to the long-term and overuse of antibiotics, poses increasingly serious threats to human lives [1]. However, the progress of discovery and production of new antibacterial drugs cannot keep up with the evolution of MDR bacteria [2]. Bacteria is prone to adhere on any biotic and abiotic surfaces and form self-protective biofilms that act as an obstacle to both the immune system and the penetration of antibiotics [3]. Therefore, it is essential to further improve killing efficiency of current antibiotics to MDR bacteria both in planktonic phases and embedded in biofilms. Recently, hydrophobic antibiotics were encapsulated into nano-drug carriers, such as polymeric micelles [4], vesicles [5], liposomes [6], inorganic nanoparticles and nanogels [7,8], to enhance bioavailability, reduce administration dose and achieve deep penetration into biofilms of conventional antibiotics. Among these nano-drug carriers, polymeric micelles were the most widely used carriers due to their tailorable structures, good blood compatibility and relatively good stability [[9], [10], [11]]. However, low delivery efficiency of polymeric micelles necessitates high dosing to achieve ideal therapeutic dosage at infectious sites [12,13]. Moreover, the majority of polymeric carriers, which serve as the primary constituents of nanomedicines, lack any therapeutic functions beyond their role as delivery vehicles. These constraints underscore the imperative for the development of effective and secure therapeutic strategies for delivering drugs to specific infectious sites.

Highly fluorinated compounds, characterized by their remarkably low surface free energy, exhibit both hydrophobic and oleophobic properties. Fluorocarbons have very low surface free energy and highly fluorinated compounds are both hydrophobic and oleophobic [14]. Therefore, polymeric amphiphiles containing fluorocarbons exhibit distinctive self-assembly characteristics in low critical aggregation concentration aqueous solutions. The powerful interactions between the fluorinated segments on the polymer substantially improve the stability of the aggregates [[15], [16], [17]]. Modifying polymers with fluoroalkyls or fluoroaromatics enhances serum stabilization, cellular uptake, endosomal escape, and intracellular drug delivery of polymeric micelle systems, thereby dramatically improving therapeutic efficacy [18,19]. It is well-established that approximately a quarter of all drugs on the market contain fluorine atoms, which are typically insoluble in aqueous solutions [20]. The drugs can be effectively loaded by the assembled fluoropolymers through the synergistic action of the fluorophilic effect and hydrophobic interactions [14]. In addition, the increased interaction between the drugs and fluorocarbon chains will reduce the premature release of the encapsulated drugs [21]. Considering these features of fluorocarbons, we hypothesize that fluorinated amphiphilic copolymers-based micelles with infectious targeting and deep biofilms penetration properties can be used as antibiotics delivery systems to enhance drug loading capacity, serum stability and reduce burst premature release of loaded drugs. In addition, fluorination mediated efficient cellular uptake may further improves the therapeutic efficacy of antibiotics [[22], [23], [24], [25]], especially for antibiotics which targeting the internal components, such as bacterial protein synthesis and nucleic acid synthesis machineries.

As a proof of concept, we prepared polymethacrylate diblock copolymers with pendant fluorocarbon chains and CB groups by RAFT polymerization, denoted PFBMA-b-PCB. As shown in Scheme 1, the amphiphilic fluorinated copolymers were assembled into micelles and antibiotics targeting bacteria DNA synthesis machineries, i.e., CIP was loaded for antibacterial and antibiofilm applications [[26], [27], [28]]. CIP loaded PFBMA-b-PCB micelle was named as CIP@FCBMs and its surface exhibits remarkable resistance and compatibility with cells under neutral physiological conditions, attributed to the zwitterionic properties of the carboxyl betaine groups. In areas of bacterial infection with high acidity, the surface charge of CIP@FCBMs undergoes a shift from negative to positive. This alteration boosts the accumulation and penetration of CIP@FCBMs nanoparticles into bacterial biofilms, while also promoting their connection to negatively charged bacterial cells. The fluorocarbon chains can enhance the bacterial cellular uptake of the nanoparticles and can greatly improve their antibacterial performances of the encapsulated antibiotics. Additionally, prevalent bacterial lipases in the microbial flora facilitated the degradation of polymeric micelles [29,30], causing the on-demand release of CIP for disinfecting bacteria. The use of nanoparticles, which reverse surface charge, release antibiotics upon request, and aid cellular uptake through fluorination, displays a particularly effective approach for combating bacterial infections and biofilms.