Integrated in silico network pharmacology and β-cyclodextrin nanosponge based delivery of nafithromycin: Mechanistic insights, controlled release, and enhanced antimicrobial activity

Nafithromycin is a next-generation macrolide antibiotic with a broad antimicrobial spectrum; however, its clinical utility is constrained by unfavorable physicochemical properties that can limit solubility, permeability, and oral bioavailability. In this study, an integrated strategy combining in silico network pharmacology with experimental formulation of a β-cyclodextrin (β-CD) nanosponge delivery system was employed to elucidate Nafithromycin’s molecular mechanisms and enhance its therapeutic performance. SwissADME analysis predicted poor oral bioavailability, attributed to high molecular weight, elevated topological polar surface area, and extensive hydrogen-bonding capacity, suggesting restricted passive absorption and blood–brain barrier penetration. Notably, these predictions contrast with reported in vivo pharmacokinetic data demonstrating effective lung distribution and macrophage uptake, underscoring the importance of formulation design and biological transport mechanisms in drug disposition. Network pharmacology analysis revealed 51 intersecting genes between Nafithromycin-associated targets and microbial infection–related pathways, indicating that its activity extends beyond direct antimicrobial effects to modulation of immune and inflammatory responses. Protein–protein interaction network analysis demonstrated dense functional connectivity, with EGFR, MTOR, KDR, BCL2, and MCL1 identified as key regulatory hubs. Molecular docking further supported Nafithromycin's multi-target potential, showing strong binding affinities, particularly with MTOR (–10.3 kcal/mol) and MCL1 (–9.2 kcal/mol). To overcome physicochemical limitations, Nafithromycin was encapsulated into β-CD nanosponges. UV–visible and FT-IR analyses confirmed successful drug incorporation, while SEM revealed a porous sponge-like morphology. Dynamic light scattering indicated a uniform nanoscale size (∼149 nm) and good colloidal stability, supported by a negative zeta potential (∼–29.9 mV). The nanosponge system exhibited high encapsulation efficiency, sustained drug release (∼83% at 24 h), notable antioxidant activity, and enhanced antifungal efficacy against Aspergillus niger and Candida albicans . Overall, this integrated approach highlights the potential of nanosponge-based delivery to improve Nafithromycin’s biological performance and therapeutic applicability.