Biomimetic Zwitterionic Micelles for Efficient Mucus Penetration and Pulmonary Targeting in Acute Lung Injury

Nebulized inhalation represents an attractive approach for pulmonary drug delivery due to its non-invasiveness and direct lung targeting capability. However, the effectiveness of conventional inhaled formulations is limited by their inability to simultaneously evade mucociliary clearance and macrophage phagocytosis, leading to suboptimal lung retention and low bioavailability. To address these challenges, a series of ultra-small zwitterionic "camouflage" micelles, Distearoylphosphatidylethanolamine (DSPE)-block-poly ( N -methacryloyloxyethyl- N, N -dimethylammonium-α-N-methylcarboxybetaine) (CB) (D-PCB n ), were developed to synergize biomimetic targeting with enhanced mucosal penetration. The micelles feature a DSPE-based core structurally modeled after dipalmitoylphosphatidylcholine (DPPC), a key pulmonary surfactant lipid, enabling biomimetic alveolar targeting. Simultaneously, a carboxybetaine-derived corona facilitates robust hydration-mediated surface lubrication for efficient mucus penetration. Among the series, the optimized D-PCB 30 variant exhibited superior mucus-permeating capacity, enhanced pulmonary deposition, and high encapsulation efficiency for dexamethasone. In vivo evaluation in a murine model following aerosol administration demonstrated significantly improved lung accumulation, extended residence time, reduced systemic distribution, and enhanced anti-inflammatory efficacy. Transcriptomic analysis further indicated modulation of critical inflammatory pathways and reprogramming of macrophage polarization (M1 to M2 phenotype), corroborating the therapeutic benefits achieved through enhanced barrier penetration. These results demonstrate the potential of D-PCB n micelles as a promising inhalable nanoplatform for targeted treatment of lung diseases. Statement of Significance Delivering therapeutics to injured lungs is hampered by mucus barriers, rapid clearance, and immune sequestration. Here, we describe ultra-small, biomimetic zwitterionic micelles D-PCBMA n (D-PCB 30 ) that combine a DPPC-mimetic DSPE core with a carboxybetaine corona to create a “camouflage-and-lubricate” nanoplatform. D-PCB 30 exhibits a low critical micelle concentration (CMC), high drug loading, and stability upon nebulization, enabling deep mucus penetration, reduced macrophage uptake, and sustained pulmonary residence. When loaded with dexamethasone (DEX) and delivered by nebulization, D-PCB 30 increases local drug deposition while reducing systemic exposure, resulting in potent attenuation of LPS-driven inflammation, preservation of alveolar architecture, and diminished fibrotic remodeling. Mechanistically, transcriptomic profiling reveals suppression of TLR/MyD88/NF-κB inflammatory circuits and induction of tissue-repair programs, alongside a shift in macrophage phenotype toward resolution. With an encouraging biosafety profile and mitigated steroid side effects, D-PCB 30 represents a clinically promising strategy to overcome pulmonary barriers and to deliver targeted, effective therapies for acute inflammatory lung disease.