Nanoparticles targeting pulmonary capillaries

Lung Disease Breakthrough: Charge-Based Nanoparticles Target Pulmonary Endothelium

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Kai Mendoza in Health & Wellness December 2025 • 4 min read.

"Revolutionary research unveils a highly efficient method for targeting lung microvasculature, paving the way for advanced gene therapies."


Pulmonary vascular disease (PVD) presents a significant challenge in both pediatric and adult medicine, demanding more effective treatment strategies. Gene therapy holds immense promise, yet the development of safe and efficient delivery systems remains a critical hurdle. Traditional viral vectors, while effective, pose risks such as immune responses and random genome integration.

Researchers have focused on non-viral delivery systems, with polyethylenimine (PEI) showing considerable potential due to its high buffering capacity, which aids in intracellular compartmentalization. However, balancing PEI's transfection efficiency with its cytotoxicity has been a key challenge. Recent studies explore modifications to lower molecular weight PEI to reduce toxicity and boost effectiveness.

Now, a new study introduces an innovative approach: functionalizing hyperbranched PEI with biological fatty acids and carboxylate-terminated poly(ethylene glycol) (PEG). This method creates nanoparticles that exhibit exceptional specificity for the pulmonary microvascular endothelium, enabling successful delivery of therapeutic mRNA. The key? Tuning the surface charge of these nanoparticles.

How Charge Modification Revolutionizes Lung-Targeted Drug Delivery

Nanoparticles targeting pulmonary capillaries

The research team synthesized novel polyplexes by modifying hyperbranched PEI with fatty acids like myristic acid, linoleic acid, and PEG. These modifications were achieved through a one-pot reaction, simplifying the process and enhancing its potential for scalability. The resulting nanoparticles demonstrated a controlled hydrodynamic size and surface charge, crucial factors for in vivo applications.

Following intravenous injection into mice, these nanoparticles exhibited remarkable specificity for the pulmonary microvascular endothelium. This targeted delivery facilitated the successful introduction of stabilized enhanced green fluorescent protein (eGFP) mRNA, showcasing the system's ability to deliver therapeutic payloads directly to lung cells.

The study's key findings include:
  • High Specificity: The nanoparticles preferentially accumulate in the lung tissue, particularly within the alveolar capillary endothelium.
  • Charge Dependence: Positive surface charge is the primary driver behind the targeting efficiency. Modifying the charge with poly(acrylic acid) or heparin significantly reduces targeting.
  • Microvascular Targeting: The nanoparticles are highly disseminated within the pulmonary microvasculature, a critical target for treating PVD.
These results underscore the importance of surface charge in directing nanoparticles to specific cell types within the lung. By carefully controlling the chemical formulation to achieve the desired surface charge, researchers can optimize drug delivery and minimize off-target effects. Live in vivo imaging, flow cytometry, and confocal microscopy confirmed these findings, providing a comprehensive picture of the nanoparticles' behavior.

Future Implications and Therapeutic Potential

This research represents a significant step forward in targeted drug delivery for pulmonary vascular diseases. By demonstrating the critical role of surface charge in directing nanoparticles to the lung endothelium, the study opens new avenues for developing more effective and selective therapies.

The ability to deliver mRNA specifically to lung cells holds promise for treating a range of conditions, including pulmonary hypertension and alveolar capillary dysplasia. Non-viral delivery systems like these offer a safer alternative to traditional viral vectors, reducing the risk of adverse immune responses and genome integration.

Further research will focus on optimizing the nanoparticle formulation, exploring different therapeutic payloads, and conducting preclinical studies to evaluate the long-term safety and efficacy of this approach. The precision targeting achieved through charge modification could revolutionize the treatment of lung diseases, offering new hope for patients with PVD.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1002/adhm.201800876, Alternate LINK

Title: Highly Efficient In Vivo Targeting Of The Pulmonary Endothelium Using Novel Modifications Of Polyethylenimine: An Importance Of Charge

Subject: Pharmaceutical Science

Journal: Advanced Healthcare Materials

Publisher: Wiley

Authors: Andrew W. Dunn, Vladimir V. Kalinichenko, Donglu Shi

Published: 2018-11-06

Everything You Need To Know

1

How does this new method specifically target lung microvasculature for drug delivery?

The innovative approach involves functionalizing hyperbranched polyethylenimine (PEI) with biological fatty acids and carboxylate-terminated poly(ethylene glycol) (PEG). This creates nanoparticles with exceptional specificity for the pulmonary microvascular endothelium, enabling successful delivery of therapeutic mRNA. The tuning of the surface charge of these nanoparticles is critical for targeted delivery.

2

What modifications are made to the nanoparticles to ensure lung-specific targeting, and how are these modifications achieved?

Researchers modified hyperbranched polyethylenimine (PEI) with fatty acids such as myristic acid and linoleic acid, along with poly(ethylene glycol) (PEG), through a simplified one-pot reaction. This resulted in nanoparticles with controlled hydrodynamic size and surface charge, essential for in vivo applications, and demonstrating high specificity for the pulmonary microvascular endothelium after intravenous injection in mice.

3

What is the role of surface charge in targeting lung tissue, and how does altering the charge affect the nanoparticle's performance?

The targeting efficiency of the nanoparticles is primarily driven by their positive surface charge. Modifying this charge with substances like poly(acrylic acid) or heparin significantly reduces their ability to target the lung tissue effectively. This highlights the critical role of surface charge in directing nanoparticles to specific cell types within the lung.

4

What are the broader implications of this research for treating pulmonary vascular diseases, and what future developments might we see?

This advancement signifies a major leap in targeted drug delivery for pulmonary vascular diseases (PVD). Understanding and leveraging the role of surface charge to direct nanoparticles to the lung endothelium opens doors for creating more effective and selective therapies. Future research can explore different charge modifications and combinations of targeting ligands to further enhance specificity and therapeutic efficacy.

5

Besides mRNA, what other types of therapeutic payloads could potentially be delivered using this surface charge-based targeting system?

While the focus is on mRNA delivery using surface charge-modified nanoparticles, the broader implications extend to other therapeutic modalities. This targeted delivery system could potentially be adapted for delivering small interfering RNA (siRNA), proteins, or even chemotherapeutic agents directly to the lung microvasculature. Further research could explore the compatibility and efficacy of delivering different types of therapeutic payloads using this charge-based targeting approach.

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