Inhalable Porous PLGA Microspheres Enable Lung-Targeted Dual-Drug Delivery for the Treatment of High-Altitude Pulmonary Hypertension

Background High-altitude pulmonary hypertension (HAPH), driven by hypobaric hypoxia–induced vasoconstriction and vascular remodeling, remains a therapeutic challenge due to the limited efficacy and systemic side effects of current treatments. This study aimed to develop a dual-drug–loaded microsphere system for targeted pulmonary delivery. Methods Porous PLGA microspheres co-loaded with hydrophilic L-arginine and hydrophobic tadalafil (PLGA-LA/Tada MSs) were fabricated using a gas-foamed double-emulsion technique. The microspheres were characterized for morphology, porosity, aerodynamic properties, and in vitro release profiles. In vivo pharmacokinetics, safety, and therapeutic efficacy were evaluated following a single intratracheal administration in a chronic hypobaric hypoxia–induced HAPH rat model. Results The PLGA-LA/Tada MSs displayed uniform spherical morphology, well-developed porosity, and favorable aerodynamic behavior (MMAD ~ 4.7 µm), supporting deep-lung deposition. In vitro, L-arginine exhibited rapid release, whereas tadalafil showed sustained release. A single intratracheal dose achieved efficient pulmonary deposition, prolonged lung retention, and reduced systemic exposure. Therapeutically, PLGA-LA/Tada MSs improved RVSP, mPAP, and Fulton’s index; mitigated fibrosis and vascular muscularization; and preserved alveolar structure. Mechanistic studies indicated restored NO/cGMP signaling, reduced oxidative stress and inflammation, and normalization of erythropoietic markers. Conclusion PLGA-LA/Tada MSs enable spatially and temporally coordinated pulmonary delivery of hydrophilic and hydrophobic agents, allowing synchronized modulation of the NO–cGMP axis. This dual-drug microsphere platform provides durable pulmonary vascular protection with minimal systemic exposure and demonstrates strong translational potential for treating HAPH and other hypoxia-driven pulmonary diseases.