Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating lung disorder characterized by activated fibroblast [1], severe inflammation [2], and accumulated extracellular matrix (ECM) [3], leading to impaired respiratory function. Pulmonary delivery offers rapid onset and reduced systemic toxicity [4]. However, the pulmonary mucus barrier, while preventing the invasion of viruses and microorganisms [5], also limits the drug's ability to reach the target site [6]. The mucus layer is rich in densely glycosylated and negatively charged mucins [7,8], and although hydrophilic or negatively charged modifications can partially improve mucus penetration [9,10], the combined effects of pathological mucus thickening, macrophage interception, and limited tissue transport continue to restrict the bioavailability of inhaled therapeutics [11]. Alveolar macrophages, acting as immune sentinels [12], are further recruited in response to IPF-associated inflammation and tissue damage [[13], [14], [15]]. and their vigorous phagocytic activity significantly reduces drug retention and therapeutic efficacy [16,17]. PEG-based evasion strategies, such as PEGylated polyplexes reported by Kim et al. [18], can reduce macrophage uptake but often compromise particle–cell interactions and limit nanoparticle accumulation in fibrotic lesions. Taken together, the conflicting physiological barrier of the lungs posed by the pulmonary mucus barrier, macrophage interception, and drug transport at the site of pulmonary fibrosis make it challenging for drugs to reach the target site effectively.

Conventional inhaled nucleic acid carriers commonly employ PEGylation to enhance hydrophilicity, thereby improving mucus penetration and reducing immune clearance. For instance, Kim et al. optimized the lipid composition and PEG ratio of nanoparticles to increase mucus permeability and mechanical stability [19]. However, excessive PEGylation weakens particle–cell interactions and limits accumulation in fibrotic lesions [20]. To enhance targeting specificity, ligand-mediated modifications have been developed to recognize receptors such as integrins or hyaluronic acid receptors, thereby improving nucleic acid uptake in pulmonary cells [21]. Such as FAP-peptide or PDGFRα-Fab' functionalization-have demonstrated improved myofibroblast targeting and anti-fibrotic efficacy [21]. Yet, the heterogeneous receptor expression in fibrotic lungs, coupled with mucus obstruction and macrophage phagocytosis [22], continues to hinder deep tissue delivery. Consequently, individual PEGylation or ligand-targeting strategies alone remain inadequate for achieving efficient nucleic acid delivery across these multiple barriers. Addressing these challenges requires an integrated strategy that simultaneously overcomes mucus thickening, macrophage interception, and other barriers to improve drug transport and enhance therapeutic outcomes in IPF.

Macrophage-hitchhiking has emerged as a promising strategy for targeted delivery [23], leveraging the innate migratory and phagocytic capacity of pulmonary macrophages to ferry therapeutics across physiological barriers and accumulate within fibrotic lesions [23]. For example, Yue et al. exploited macrophage homing to inflamed lungs to release intracellular drugs in situ [24], and Wang et al. demonstrated that liquid‑nitrogen-treated M1 macrophages preserve inflammation-targeting while limiting cytokine release in acute lung injury [25]. Building on these insights, our study harnesses macrophage-mediated transport to overcome the pulmonary mucus barrier and enhance drug delivery efficiency in IPF.

Herein, building on the inspiration drawn from the migration of macrophages towards fibrotic regions post-IPF onset, we propose an innovative strategy that departs from conventional macrophage evasion tactics (Scheme 1). Conceptualizing macrophages as drug delivery carrier, inhalable nanosystem loaded with the interleukin-11 (IL-11) antisense oligonucleotide (ASO) is effectively taken up by macrophages via natural cell adhesion, accompanied by macrophages crossing the mucus barrier. Within the macrophages, the nanosystem achieves lysosomal escape through the proton sponge effect, followed by IL-11 ASO release through the reactive oxygen species (ROS) response. More importantly, a motif of promoting extracellular vesicle (EV) encapsulation on ASO is employed, guiding the ASO into macrophage-derived EV, and allowing for the efficient unloading of ASO at the targeted sites. Leveraging the natural crosstalk between macrophage-derived EV and fibroblasts, the IL-11 ASO is then effectively delivered to fibroblasts, significantly reducing the expression of IL-11 and achieving a more potent therapeutic effect in treating IPF. In the realm of translational applications, this pioneering strategy holds promise for broad therapeutic intervention, including challenges in drug delivery for various respiratory conditions with mucus barriers and macrophage interception.