Spatiotemporally programmed biomimetic liposome coordinates vascular and immune modulation in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) remains a progressive and fatal vascular disease despite substantial advances in vasodilator-based therapies. Combining anti-inflammatory intervention with established vasodilator treatment represents a promising disease-modifying strategy for PAH. Here, persistent IL-6-associated inflammatory remodeling has been identified as an important driver of pulmonary vascular remodeling that persists despite standard vasodilator therapy. Guided by this insight, a biomimetic, reactive oxygen species (ROS)-responsive nanoplatform, Lipo@MM-Maci-Pep@TCZ, was developed for the coordinated delivery of the vasodilator macitentan and the anti-IL-6 receptor antibody tocilizumab to diseased pulmonary vasculature. This programmable core–shell nanoplatform integrates a macitentan-loaded diselenide liposomal core for ROS-triggered drug release, macrophage membrane cloaking for inflammation-guided vascular targeting and endothelial interaction, and an RGD-containing self-assembling peptide interface for tocilizumab loading, thereby enabling enhanced antibody encapsulation and prolonged pulmonary retention. Lipo@MM-Maci-Pep@TCZ executes a sequential delivery cascade involving adhesion to inflamed endothelium, transendothelial transport, lesion-specific disassembly, and synchronized drug release within the immune-vascular microenvironment. In two independent experimental PAH models, this dual-drug nanotherapy reduced right ventricular systolic pressure, right ventricular hypertrophy, pulmonary vascular remodeling, fibrosis, macrophage infiltration, and smooth muscle cell proliferation, outperforming monotherapy and free-drug combinations. Transcriptomic analysis revealed the coordinated suppression of inflammatory signaling and of pathogenic smooth muscle cell remodeling programs, the reprogramming of macrophage-associated inflammatory pathways, and the restoration of endothelial homeostasis through simultaneous inhibition of endothelin- and IL-6-driven signaling. Collectively, these results demonstrate a microenvironment-responsive combinatorial nanomedicine strategy that integrates vasodilatory and immune-targeted therapy, establishing a promising therapeutic framework for PAH and potentially other inflammatory vascular diseases.