Bacterial pneumonia is a globally challenging infectious disease characterized by high incidence and mortality rates [1,2]. Antibiotics play a vital role in the treatment of bacterial infections, but their lack of specificity and the emergence of drug-resistant bacteria have significantly diminished their therapeutic efficacy [3,4]. Additionally, protective biofilms formed by bacteria block the interaction between drugs and bacteria, further reducing the effectiveness of antibiotics such as in the case of Pseudomonas aeruginosa [5,6]. On the other hand, bacterial infections often involve inflammatory progression, and in the late stages of pneumonia, the continuous release of inflammatory mediators leads to alveolar damage and interstitial fibrosis, impairing the lung's gas exchange capacity and causing irreversible damage to pulmonary function [7,8]. Although antibiotics can reduce the severity of bacterial lung infections, their ability to combat inflammatory responses remains minimal [[9], [10], [11]]. Therefore, the development of novel drug delivery systems capable of penetrating, delivering drugs to the lesion site with targeted precision, and exhibiting anti-inflammatory properties has become a key focus [12].

Ciprofloxacin is a third-generation quinolone antibiotic that works by inhibiting DNA topoisomerase to prevent bacterial DNA replication, thereby exerting a bactericidal effect [13,14]. In recent years, the research and application values of active components from natural medicines in the fields of antibacterial and anti-inflammatory activities have received extensive attention [15,16]. Andrographolide is an active component derived from the natural herb Andrographis paniculata, which exerts anti-inflammatory effects by inhibiting the NF-κB signaling pathway. Additionally, it further reduces the inflammatory response by regulating macrophage polarization [17,18]. The combination of Ciprofloxacin and andrographolide not only demonstrates synergistic effects in antibacterial and anti-inflammatory activities but also reduces the risk of bacterial resistance development caused by long-term monotherapy with antibiotics.

The significant application potential of micelles in drug delivery has attracted considerable attention, as their ability to effectively evade clearance by the reticuloendothelial system (RES) allows them to prolong blood circulation time and enhance the permeability and retention (EPR) effect in inflammatory tissues [[19], [20], [21]]. In recent years, drug delivery formulations have been designed based on the differences in microenvironmental characteristics between diseased sites and normal tissues, aiming to achieve targeted delivery and intelligent responsive release [[22], [23], [24]]. Bacterially infected lungs often exhibit mild acidity (pH 5.4), thus antimicrobial formulations developed for such weakly acidic environments have attracted significant attention [25]. Maohua Chen et al. developed pH-responsive micelle capable of releasing both vancomycin (Van) and ciprofloxacin (Cip), designed for treating Pseudomonas aeruginosa-induced bacteremia [26]. Shuolin Cui et al. developed pH-responsive vesicles designed to eradicate Pseudomonas aeruginosa biofilms [27]. Acid responsiveness in micelles is achieved by integrating acid-labile groups into the hydrophobic block, necessitating appropriate polymer-drug conjugation sites. However, the lack of suitable binding sites in many drugs often requires complex post-modification processes, escalating synthetic complexity.

Here, we designed a nanomicelle (FA-Cip/Ag-Ms) to address the above issues.The micelle was constructed via self-assembly of the synthesized amphiphilic block copolymer PEG-Hyd-PCL in aqueous media, where the hydrazone (Hyd) linkage within the copolymer backbone confers pH-responsive characteristics to the nanocarriers.Leveraging hydrophilic-hydrophobic interactions, Cip and Ag were encapsulated within the micellar core to exert synergistic antimicrobial and anti-inflammatory effect. Given the overexpression of folate receptors on activated macrophages and the membranes of proliferating bacteria, FA is incorporated as a targeting ligand onto the micelle surface to enhance target specificity for pathological sites.This dual-functional design integrates active targeting and pH-responsive degradation, offering a promising strategy to improve local drug accumulation, reduce systemic toxicity, and enhance therapeutic outcomes for infectious diseases.