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Acute lung injury (ALI) involves alveolar-capillary barrier disruption, inflammatory amplification, oxidative stress, and loss of alveolar architecture. This study developed pH-responsive chitosan-coated spanlastic nanovesicles as a pharmaceutical platform for lung-targeted delivery of Brilliant Blue G (BBG), a P2X7 receptor antagonist. BBG-loaded spanlastics were prepared by thin-film hydration and optimized using a 2³ factorial design assessing the effects of Span 60:BBG ratio, Span 60:edge activator ratio, and edge activator type on vesicle size, zeta potential, and entrapment efficiency. The optimized formulation was coated with chitosan to achieve surface cationization, enhance colloidal stability, support mucoadhesive interaction with lung tissue, and provide pH-responsive release. BBG-Ch-SPNs exhibited nanoscale size, positive zeta potential, high entrapment efficiency, acceptable hemocompatibility, and sustained drug release, with greater BBG liberation under acidic conditions relevant to inflamed lung microenvironments. Release kinetic analysis supported diffusion-controlled release with pH-dependent polymer relaxation, while stability testing confirmed preservation of vesicle size, surface charge, and drug entrapment over three months. In vivo, BBG-Ch-SPNs improved pulmonary retention and lung exposure compared with free BBG and uncoated spanlastics, demonstrating enhanced lung-targeting efficiency. Therapeutically, BBG-Ch-SPNs reduced BALF protein leakage, LDH activity, NOx levels, and leukocyte influx while preserving alveolar architecture and limiting septal thickening, edema, and inflammatory infiltration. These effects were accompanied by restored antioxidant defenses and suppression of P2X7R/NF-κB/NLRP3 inflammasome signaling. Overall, chitosan-coated spanlastics improved BBG formulation performance, pH-responsive delivery, pulmonary biodistribution, and therapeutic efficacy, supporting their potential as a targeted nanotherapeutic system for ALI.