From nanotechnology to immunomodulation: emerging strategies targeting macrophages in high altitude pulmonary hypertension.

High altitude pulmonary hypertension (HAPH) is a public health issue in high-altitude regions, characterized by increased pulmonary artery pressure, pulmonary vascular remodeling, and right heart failure, leading to the high incidence rate and high mortality. Current therapies can alleviate patient symptoms but provide limited control over disease progression. Immune regulation has gained recognition as a central driver of HAPH. Among immune cells, macrophages, as key immune regulators in the lung, orchestrate HAPH pathogenesis through recruitment, M1/M2 polarization, inflammatory activation, metabolic reprogramming, and crosstalk with pulmonary vascular cells. Targeting macrophages has emerged as a promising therapeutic strategy. Nanoplatforms provide powerful tools to enable precise targeting and functional modulation of macrophages in HAPH, as nanoplatforms such as liposomes, polymeric nanoparticles, and exosomes enable targeted delivery and controlled release, thereby facilitating precise regulation of the pulmonary immune microenvironment, including both macrophages and pulmonary vascular cells. Recent advances in nanoplatforms have enabled the development of macrophage focused precision interventions. In this review, we first outline the pathogenic roles of macrophages in the development and progression of HAPH. We then summarize the therapeutic potential of nanoplatform-based approaches in HAPH, with a particular focus on emerging nanomaterial-based strategies that enable targeted modulation of macrophage function. We argue that nanoplatform assisted macrophage immunotherapy holds strong potential to move HAPH treatment from symptomatic management toward mechanistic and precision interventions.