Nanotherapeutic strategies for fibroblast targeted treatment of pulmonary fibrosis

1. Introduction

Interstitial lung diseases (ILDs) are characterized by inflammation and/or fibrotic scarring of the lung parenchyma, often leading to progressive dyspnea and, ultimately, end-stage respiratory failure [1]. Among ILDs, idiopathic pulmonary fibrosis (IPF) is the most common and severe form with a 5-year mortality rate of approximately 50% [2]. The pathogenesis of IPF is driven by excessive deposition of extracellular matrix (ECM) proteins, which progressively impair lung function.

Despite advances in understanding IPF pathogenesis, no therapy has been shown to effectively halt disease progression or reverse established fibrosis [3]. Studies have shown that chronic alveolar epithelial injury followed by abnormal ECM accumulation, primarily produced by persistently activated fibroblasts, is central to disease progression. Under normal physiological conditions, transient fibroblast activation is required for wound healing. In contrast, pathologically activated fibroblasts continuously produce collagen rich, stiff ECM, leading to irreversible architectural distortion. Therefore, selectively targeting abnormally activated, pro-fibrotic fibroblasts represents a promising strategy to effectively mitigate lung fibrosis. Transgenic murine models have highlighted the therapeutic potential of targeting these activated fibroblasts [4]. Recent single cell RNA sequencing (scRNAseq) analysis further identified distinct pathological fibroblast subtypes closely associated with collagen production and fibrotic remodeling. However, translating such cell (subtype)-specific approaches into clinically viable treatments remains a major challenge. In this editorial review, we examine recent nanotechnology developments aimed at targeting activated fibroblasts and limiting ECM production, along with key limitations and future directions.

2. Heterogeneous fibroblast populations and their functions

Lung alveoli serve as the primary sites for gas exchange. Each alveolus is composed of diverse cell types, including epithelial, endothelial, and mesenchymal cells [5]. Among these, mesenchymal cells play key roles in lung development, tissue repair, and remodeling [5,6]. Fibroblasts, the principal mesenchymal cells responsible for ECM production, play a central role in both wound healing and fibrosis. As such, targeting specific pathologic mesenchymal cell populations has become a focal point for therapeutic intervention. Platelet-derived growth factor receptor-α (PDGFR-α) is broadly used as a cell surface marker to identify mesenchymal cells in fibrotic lesions [7], while α-smooth muscle actin (α-SMA) is widely recognized as a marker of myofibroblasts [8]. Recently, technologic advances, particularly scRNAseq approaches that allow the characterization of cellular heterogeneity, have revealed multiple collagen-producing fibroblast subtypes in fibrotic lungs [5,9], highlighting the opportunity for subtype-specific therapeutic targeting. For example, CD82 marks lipofibroblasts, CD239 identifies myofibroblasts, and CD55 is associated with EBF1⁺ fibroblasts [9]. Among these subtypes, alveolar fibroblasts, which support alveolar type II epithelial cells and maintain alveolar homeostasis, emerge as predominant precursors of an activated pathologic fibroblast population in the setting of both IPF and murine bleomycin-induced pulmonary fibrosis [5]. This activated fibroblast population, marked by expression of CTHRC1⁺ (collagen triple helix repeat-containing 1), has been strongly implicated in pathologic collagen overproduction in fibrotic lungs [5,9]. Importantly, CTHRC1⁺ fibroblasts isolated from IPF lungs show markedly elevated collagen expression compared to those from healthy controls [5]. Beyond their fibrogenic capacity, IPF fibroblasts are characteristically resistant to apoptosis [10], and their persistent accumulation is a hallmark of progressive fibrosis. Thus, precise identification and selective targeting of pathogenic fibroblast (sub)types that drive fibrogenesis hold promise for the development of effective anti-fibrotic therapies.

3. Targeted therapeutic approaches using novel nano-sized drug carriers: nanotherapies

Despite FDA approval of pirfenidone, nintedanib, and nerandomilast for IPF, no curative or highly effective therapy currently exists. All three drugs, when administered systemically, are associated with off-target toxicities. To improve therapeutic efficacy through targeted delivery, several key challenges must be addressed: (1) the identification and characterization of specific cell (sub)types that drive lung fibrosis; (2) the discovery and validation of reliable surface markers uniquely expressed by these pathogenic cell populations; (3) the design of drug carriers capable of efficiently reaching and being selectively internalized by fibroblasts within the collagen ECM-rich fibrotic lung microenvironment; (4) the development of delivery systems that are biocompatible, exhibit minimally toxicity, and safe for clinical application.

To accommodate these needs, nanoparticle (NP)-based drug delivery systems offer a promising solution to overcome these challenges by enabling targeted, site-specific, and long-acting therapies that improve efficacy and patient compliance [11,12]. Nanoparticles can be classified into three main categories based on their composition: organic, carbon-based, and inorganic [13]. Inorganic materials such as gold, iron, and silica have been used to synthesize nanostructured materials for drug delivery and imaging applications [13]. In contrast, organic nanosized drug carriers such as lipid-based, peptide-based, and polymeric nanocarriers are more biocompatible, and have been used to specifically target fibroblasts in lung fibrosis.

4. Pros and cons of nano-sized drug carriers

For targeted therapy, nano-sized, biocompatible, and biodegradable organic nanocarriers are highly suitable for pulmonary drug delivery. Liposomes, exosomes, and lipid nanoparticles (LNPs) belong to the lipid-based class, whereas PLGA nanoparticles, chitosan nanoparticles, and dendrimers are representative polymeric nanocarriers (PNPs). Lipid-based nanocarriers offer excellent biocompatibility, biodegradability, and versatility, with strong potential for controlled drug release and cell type – specific targeting. However, they can be destabilized by mucociliary clearance and alveolar macrophage uptake [14]. In addition, inefficient cellular uptake by fibroblasts and limited stability during aerosolization are recognized challenges. Despite their promising potential as targeted drug carriers, particularly in the form of exosomes, limitations such as low yield, poor reproducibility, limited stability, and low drug-loading capacity remain major hurdles to clinical translation. PNPs provide advantages such as controlled and sustained drug release, high biocompatibility, biodegradability, and mechanical stability, along with reliable surface modification for targeted delivery [15,16]. Nonetheless, they face several drawbacks, including variable drug-loading efficiency, high production costs, and instability during aerosolization [16]. Peptide-based nanocarriers can be rationally designed and readily modified to recognize specific cell-surface receptors, such as integrins, PDGFR-α, and fibroblast activation protein (FAP), and exhibit low immunogenicity-an important advantage. However, they are susceptible to enzymatic degradation (e.g., by proteases), have relatively short in vivo half-lives, and may elicit immune responses in certain contexts. Furthermore, their limited extracellular matrix (ECM) penetration and reduced fibroblast uptake constrain their overall therapeutic efficacy [17].

5. Fibroblast specific targeted nanotherapeutics

Among the diverse nano-sized carriers explored for therapeutic applications in lung fibrosis, glycochitosan nanoparticles (CNPs), derived from chitosan, have emerged as a promising platform owing to their capacity to efficiently encapsulate siRNAs and other therapeutic agents [18]. CNPs exhibit high biocompatibility and versatility in theranostics, an integrated approach that combines diagnostics and therapeutic functions. Notably, CNPs demonstrate enhanced uptake by human lung fibroblasts cultured on type I collagen matrices, supporting their potential applicability in fibrotic lung disease [19]. Furthermore, CNPs loaded with anti-neoplastic drugs or fluorescent imaging agents displayed favorable pharmacokinetics and cell-targeting capabilities [20]. Advancing this approach, a peptide-targeted methoxy polyethylene glycol–poly(lactic-co-glycolic acid) (mPEG–PLGA) NP system was recently developed, carrying both the myocardin-related transcription factor (MRTF) inhibitor CCG-1423 and a near-infrared fluorophore (CyAl5.5) [21]. Functionalized with the RVYIHPI peptide, originally designed to home to the myocardium, the system successfully localized to fibrotic lungs in bleomycin-injured mice. In this study, the peptide was designed to target Angiotensin 2 receptor, which had been shown previously to be upregulated on activated fibroblasts in IPF [22]. Although this study highlights the potential of “peptide-guided nanoparticles” to enhance selective delivery of anti-fibrotic agents, structural instability, toxicity, unreliable membrane permeability, and limited bioavailability still need to be addressed [23].

More recently, engineered exosomes have emerged as innovative organic delivery vehicles with potential for IPF treatment, particularly due to their ability to reduce oxidative stress [24]. Sun et al. developed a hybrid system combining clodronate (CLD)-loaded liposomes with fibroblast-derived exosomes (EL-CLD), which demonstrated fibroblast-homing properties and preferential accumulation in fibrotic lungs [12]. Although cell-specific targeting through surface modification remains a limitation, exosome engineering holds strong promise for IPF therapeutics. Recent work has further demonstrated that inhalable, pH-responsive liposomal nanoparticles targeting myofibroblasts and co-loaded with nintedanib and siRNA against interleukin-11 (IL-11) could effectively deactivate myofibroblasts and reduce ECM deposition by 50% [25]. Another independent study corroborated these findings by demonstrating that inhalable nanoparticles delivering siRNA targeting IL-11 suppressed fibroblast differentiation and fibrosis in vivo [26]. Furthermore, follow-up research by the same group developed a “LOOP”-optimized lipid nanoparticle (iLNP-HP08^LOOP) encapsulating mRNA encoding an IL-11 single-chain variable fragment (scFv). Both intravenously administered IL-11 scFv and inhaled scFv@iLNP-HP08LOOP significantly inhibited fibroblast activation and ECM production in a bleomycin-induced lung fibrosis model [27]. Another innovative advance used mRNA-loaded lipid nanoparticles (LNP-mRNA) to generate CAR T cells, which effectively ablated activated fibroblasts and ameliorated fibrosis in the bleomycin model [28], suggesting that NP-mRNA therapy may help restore pulmonary structure and function. More recently, inhalable, pH-responsive liposomes (FL-NI) targeting fibroblast activation protein (FAP)-expressing myofibroblasts have been developed to enable the effective co-delivery of nintedanib and siIL11, a small interfering RNA that silences IL-11 [26,29]. If current limitations such as surface charge alteration and potential destabilization are addressed, this approach could exert significant anti-fibrotic effects, including enhanced myofibroblast deactivation, reduced pathological collagen deposition, and promotion of epithelial tissue repair.

6. Future prospects

Currently, FDA-approved therapies have not been shown to halt or reverse the fibrotic process, highlighting an urgent need for novel therapeutic strategies with enhanced specificity. Nanotechnology-based drug delivery strategies hold increasing potential for enabling targeted, efficient, and safer therapeutic interventions for IPF. However, several key limitations associated with the current nanocarrier platform must be addressed. First, the identification of reliable pathogenic fibroblast (sub)type-specific markers for nanoparticle (NP) delivery is critical. The characterization of fibrosis-specific cell surface markers could substantially minimize off-target effects in non-fibrotic tissues. Second, the establishment of proven safe drug delivery platforms remains a priority. Achieving this requires optimization of formulation parameters, including carrier design, particle size distribution, drug release kinetics, and aerosol stability. Third, the development of effective personalized drug delivery systems tailored to patients with lung fibrosis is essential. Identifying patient-specific biological signatures through advanced “multi-omics” approaches could enable the design of reliable, controlled, and cell type-specific nanotherapeutics. Finally, the high cost of NP preparation and lack of standardization remain barriers to clinical translation and accessibility. Developing cost-effective and reproducible production strategies such as optimization of concentration parameters, refining nanoprecipitation techniques, and establishing scalable fabrication processes could help overcome these challenges. Continued innovation in nano-sized drug delivery system holds great potential to transform the therapeutic landscape of IPF, paving the way for personalized and effective treatment strategies in the near future.

Funding Statement

Financial support was received from: U.S. Department of Health and Human Services, National Institutes of Health, OSU Department of Internal Medicine Pilot grant.

Author contributions

Richard S Nho and Rachel S Knipe jointly wrote the original and revised manuscript.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.