Advanced biomaterials are enabling precise drug delivery to fibrotic lung tissue, offering new hope for patients with this progressive and fatal disease.
Imagine trying to breathe through a mesh that gradually becomes more clogged and stiff—this is the daily reality for millions living with pulmonary fibrosis (PF), a progressive and fatal lung disease. Characterized by excessive scar tissue buildup in the lungs, PF stiffens lung tissue, impairing gas exchange and ultimately leading to respiratory failure. With a median survival of just 3-5 years post-diagnosis and over 90% of preclinical drug candidates failing in human trials, PF represents one of medicine's most pressing challenges 1 2 .
Median survival post-diagnosis for pulmonary fibrosis patients
Current FDA-approved drugs pirfenidone and nintedanib can slow but not stop or reverse disease progression, while often causing significant side effects that limit patient tolerance. The problem largely lies in delivery—how to get the right therapeutic dose to the precise location of damage without harming healthy tissue. This is where targeted drug delivery systems (DDS) using advanced biomaterials are emerging as a revolutionary approach 3 4 .
"The fight against pulmonary fibrosis is increasingly becoming a delivery challenge. While discovering effective therapeutic compounds remains crucial, the key to unlocking their potential lies in our ability to deliver them precisely to where they're needed."
In this article, we'll explore how scientists are designing sophisticated biomaterial-based systems to outsmart fibrosis, delivering treatments exactly where and when they're needed most.
The lungs present a formidable delivery challenge. Their natural defense mechanisms—including mucociliary clearance, coughing, and a complex branching structure—effectively keep pathogens out but also prevent medicines from reaching damaged areas. In PF, this problem is exacerbated by the pathological tissue itself:
Acts as a physical barrier to drug penetration, preventing therapeutics from reaching affected cells.
Patterns in fibrotic regions limit systemic drug delivery to the areas that need treatment most.
Different cell types need to be targeted simultaneously for effective treatment.
The limitations of conventional treatments highlight these delivery challenges. Pirfenidone requires taking 9 pills daily with frequent side effects including nausea and fatigue, while nintedanib can cause diarrhea and liver problems 4 . These issues stem from non-specific drug distribution throughout the body rather than targeted delivery to diseased lung tissue.
Targeted drug delivery systems use specially engineered materials to overcome biological barriers. For pulmonary fibrosis, researchers are developing several promising approaches:
Polymeric nanoparticles and micelles offer a versatile platform for drug delivery. These tiny structures (typically 20-200 nanometers) can be engineered to encapsulate drugs and release them in response to specific conditions in fibrotic tissue, such as increased enzyme activity or altered pH levels 5 6 .
Recent research has explored nanoparticles carrying Rho kinase inhibitors, Smad signaling pathway inhibitors, and JNK pathway inhibitors—all showing promise in preclinical models but limited by delivery challenges 4 .
Hydrogels—three-dimensional networks of water-swollen polymers—provide an excellent platform for sustained drug delivery in the lung. These biomaterials can be designed to respond to specific physiological triggers, releasing their therapeutic payload gradually over time 5 9 .
Perhaps the most innovative approach uses biological carriers—natural delivery systems repurposed for medicine. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as particularly promising. These nanoscale lipid-bilayer particles naturally carry bioactive molecules—proteins, lipids, and nucleic acids—from parent cells to recipient cells, influencing their behavior 7 .
Lipid bilayer membrane enclosing therapeutic cargo
These vesicles naturally accumulate in lung tissue due to the organ's extensive capillary network and first-pass filtration effect, making them ideal for pulmonary applications 7 .
To develop better treatments, scientists first needed better models to study the disease. A groundbreaking study published in Acta Biomaterialia in 2025 created a sophisticated 3D human lung model that replicates key features of early pulmonary fibrosis, providing a platform for testing new therapies 1 8 .
They used induced pluripotent stem cell-derived alveolar epithelial type II cells (iATII)—the progenitor cells responsible for maintaining the lung's gas-exchange surface—alongside human pulmonary fibroblasts.
iATII cells were formed into spheroids using magnetic nanoparticle-based aggregation to replicate the acinar structure of human alveoli.
These spheroids were embedded together with fibroblasts in specially engineered poly(ethylene glycol) norbornene (PEG-NB) hydrogels with tunable mechanical properties.
The team created two different hydrogel stiffnesses: soft (∼5 kPa) mimicking healthy lung tissue and stiff (∼19 kPa) matching the mechanical properties of fibrotic lung.
To trigger fibrotic responses, they exposed the models to a "fibrosis cocktail" of pro-fibrotic cytokines and growth factors.
The experiments yielded crucial insights into fibrosis development:
| Gene Type | Specific Genes | Change in Stiff Hydrogels + Fibrosis Cocktail | Biological Significance |
|---|---|---|---|
| ATII Markers | SFTPC | Downregulated | Loss of specialized alveolar function |
| Fibroblast Activation Markers | α-SMA, Collagen-I | Upregulated | Excessive matrix production |
| Transitional Cell Markers | Keratins, Claudin-4 | Upregulated | Stalled epithelial repair |
Table 1: Gene Expression Changes in Fibrotic Models vs. Healthy Models
| Parameter Measured | Effect of Nintedanib | Therapeutic Implication |
|---|---|---|
| Fibroblast activation genes | Downregulated | Reduced scar-forming activity |
| Transitional alveolar cell markers | Upregulated | Improved epithelial repair capacity |
| ATI cell markers | Upregulated | Restoration of differentiation potential |
Table 2: Response to Nintedanib Treatment in Stiff Hydrogel Models
The research team discovered that the combination of stiff microenvironment and pro-fibrotic biochemical cues most effectively recapitulated the gene expression patterns seen in human fibrotic lung tissue. This highlights the critical role of mechanical signals in driving disease progression—something previous 2D models on plastic dishes couldn't capture 1 .
When they tested nintedanib, the drug not only reduced fibroblast activation but also appeared to promote epithelial repair—suggesting benefits beyond what was previously understood. This demonstrates the value of physiologically relevant models for uncovering new biology and testing treatments 8 .
Developing these advanced models and delivery systems requires specialized materials and reagents. Below is a table of key components researchers use to study and treat pulmonary fibrosis:
| Reagent/Category | Specific Examples | Function in Research |
|---|---|---|
| Hydrogel Platforms | PEG-NB, Hyaluronic acid, Collagen, Fibrin | Provide 3D microenvironment with tunable properties |
| Cell Sources | iPSC-derived ATII cells, Primary pulmonary fibroblasts, Mesenchymal stem cells | Recreate human physiology and disease responses |
| Pro-fibrotic Stimuli | TGF-β, TNF-α, IL-1β, MMPs | Induce fibrotic responses in experimental models |
| Therapeutic Agents | Nintedanib, Pirfenidone, Signaling pathway inhibitors | Test anti-fibrotic efficacy in screening platforms |
| Characterization Tools | Matrix metalloproteinase-degradable peptides, RGD adhesion peptides, Antibodies for markers (α-SMA, SFTPC) | Enable cell-matrix remodeling and phenotype assessment |
| Delivery Vehicles | Polymeric nanoparticles, Liposomes, Extracellular vesicles, Micelles | Transport therapeutics to specific cellular targets |
Table 3: Research Reagent Solutions for Pulmonary Fibrosis Studies
This toolkit enables researchers to build increasingly sophisticated models that better replicate human disease, accelerating the development of more effective treatments 1 6 7 .
As biomaterial technologies advance, we're moving toward increasingly sophisticated approaches:
The next generation of delivery systems will likely incorporate diagnostic and therapeutic functions in single platforms—an approach called "theranostics." Imagine a nanoparticle that not only delivers treatment but also reports back on its location and effectiveness, allowing doctors to monitor and adjust therapy in real time 9 .
With the ability to create patient-specific lung models using iPSC technology, researchers can now test which drug and delivery system combinations work best for individual patients before prescribing treatments. This personalized approach could dramatically improve outcomes while reducing side effects 1 8 .
FDA-approved drugs slow but don't stop disease progression. Biomaterial research advances in preclinical models.
First targeted delivery systems enter clinical trials. Personalized medicine approaches validated in research settings.
Combination therapies using multiple biomaterial platforms. First theranostic approaches in clinical testing.
Disease modification and potential reversal through advanced biomaterial strategies. Widespread personalized treatment approaches.
The fight against pulmonary fibrosis is increasingly becoming a delivery challenge. While discovering effective therapeutic compounds remains crucial, the key to unlocking their potential lies in our ability to deliver them precisely to where they're needed. Advanced biomaterials—from engineered hydrogels that replicate diseased environments to natural extracellular vesicles that serve as ideal delivery vehicles—are revolutionizing this field.
As these technologies continue to evolve, the prospect of not just slowing but potentially reversing pulmonary fibrosis becomes increasingly plausible. For the millions struggling with this devastating disease, these biomaterial-based delivery systems represent more than scientific innovation—they represent hope for easier breaths and longer lives.
To learn more about recent developments in pulmonary fibrosis research, consult the scientific references cited throughout this article and consider supporting organizations dedicated to respiratory health and research.