Genotype-guided liposome engineering for precision pulmonary therapy: Linking genetic variants to nanocarrier design and clinical translation

Abstract

Inhalable liposomal nanomedicines hold transformative potential for the treatment of pulmonary diseases, yet their clinical translation is hindered by formulation instability, unpredictable lung deposition, and the absence of patient-specific design criteria. Conventional one-size-fits-all approaches fail to accommodate the genetic heterogeneity that governs disease pathogenesis and therapeutic response. This review establishes a pharmacogenomics-driven engineering framework in which patient-specific genetic variants serve as the foundational design parameters for inhalable liposomes. Within this framework, clinically actionable polymorphisms are translated into formulation specifications: the MUC5B rs35705950 variant, associated with hyper-viscous mucus, requires surface engineering with muco-penetrating polymers to enable diffusion through the airway barrier; loss-of-function CYP3A4 polymorphisms, which reduce drug metabolism, necessitate sustained-release lipid compositions to prevent toxicity; GSTM1 null genotypes, characterized by impaired oxidative stress response, demand antioxidant co-encapsulation strategies; and EGFR-mutant lung cancers require pH-responsive, ligand-targeted liposomes for on-demand drug release in the acidic tumor microenvironment. Advanced material engineering and drying technologies are strategically selected to preserve these genetically informed specifications during manufacture. A tiered bioassessment cascade, comprising regulatory-grade cascade impaction, epithelial barrier integrity assays, and high-resolution molecular imaging, validates that aerodynamic performance and targeted biodistribution align with predefined genetic criteria. By synthesizing pharmacogenomics, rational material design, and predictive analytics into a unified workflow, this framework transforms liposome engineering from an empirical process into a precision discipline. Translational scalability is addressed through a modular platform strategy that enables cost-effective, genotype-adaptable production. This convergent approach provides an operational foundation for next-generation inhalable nanotherapies calibrated to the individual molecular landscape of each patient.