Lipid nanoparticles (LNPs) have revolutionized the field of RNA therapeutics by enabling safe and effective delivery of nucleic acids into cells. However, traditional LNP systems are primarily optimized for hepatic delivery, as they naturally accumulate in the liver after systemic administration. While this has facilitated breakthroughs in liver-targeted therapies, it has also posed significant challenges for expanding RNA-based medicine to extrahepatic tissues and organs. To address this unmet need, Alfa Chemistry has developed a proprietary extrahepatic delivery platform, which enables precise and efficient delivery of RNA molecules to tissues beyond the liver, such as the spleen, lung, skin, and immune cells. This innovation represents a major step forward in unlocking the therapeutic potential of RNA technologies across a much broader spectrum of diseases.
Fig. 1. LNPs to deliver RNA to extrahepatic organs[1].
LNP Extrahepatic Delivery Challenges
The delivery of RNA therapeutics to non-liver tissues presents unique scientific and technological hurdles.
- First, conventional LNP formulations exhibit natural tropism to hepatocytes due to their interactions with apolipoprotein E (circulating LNPs can rapidly adsorb apolipoprotein E (ApoE), which mediates uptake into hepatocytes through the low-density lipoprotein receptor (LDLR) pathway) and the liver's role in clearing nanoparticles from circulation.
- Second, achieving selective accumulation in extrahepatic organs requires overcoming biological barriers such as vascular permeability, extracellular matrix density, and cellular uptake specificity.
- Third, once internalized, LNPs often face the bottleneck of inefficient endosomal escape, with only a small fraction of RNA cargo reaching the cytoplasm to exert its function.
- Finally, stability and immune compatibility must be optimized, as non-liver organs often have different sensitivities to nanoparticle composition and immune activation.
These challenges explain why extrahepatic delivery remains one of the most difficult frontiers in nanomedicine and RNA therapy development.
Strategies for Designing LNPs to Deliver RNA to Extrahepatic Organs
To successfully extend delivery beyond the liver, LNPs may be engineered with innovative design strategies:
- Lipid Composition Optimization: By tuning ionizable lipids, helper lipids, and PEGylated lipids, the physicochemical properties of LNPs can be adjusted to favor circulation time, stability, and biodistribution.
- Surface Engineering: Incorporation of targeting ligands or charge modifications can redirect LNPs to specific cell types in the spleen, lung, skin, or immune system, enhancing tissue specificity.
- Particle Size and Shape Control: Modifying nanoparticle size influences biodistribution, with smaller particles more capable of penetrating dense tissue structures and certain barriers.
- Immune Modulation: Rational design to minimize innate immune activation ensures tolerability while maximizing therapeutic efficacy across different tissue environments.
Through these strategies, it is possible to develop LNP systems that overcome the natural liver bias and achieve effective therapeutic concentrations in extrahepatic tissues.
Our Extrahepatic Delivery Platform
Our platform is built upon proprietary LNP technology and our patented library of novel ionizable lipids. By integrating rational lipid design, novel formulation processes, and advanced targeting methodologies, we have achieved efficient delivery of RNA therapeutics to multiple extrahepatic tissues:
- Spleen: Targeting immune-related disorders by modulating RNA expression within splenic immune cell populations.
- Lung: Enabling local and systemic therapies for pulmonary diseases through optimized biodistribution.
- Skin: Facilitating RNA delivery for dermatological applications, wound healing, and immunotherapy.
- Immune Cells: Unlocking the potential of in vivo immune modulation for cancer immunotherapy and vaccine development.
In addition to tissue-specific targeting, our platform incorporates design features that enhance endosomal escape efficiency, ensuring that a greater proportion of RNA payload successfully reaches the cytoplasm for functional activity. Our platform has demonstrated strong performance across a range of RNA modalities, including mRNA, siRNA, and circRNA, as well as gene editing tools. These capabilities make it a versatile and powerful solution for researchers and developers seeking to expand RNA therapies beyond liver-targeted applications.
How Can Our Platform Help You?
Our extrahepatic delivery platform offers partners and clients a reliable foundation for accelerating research and therapeutic development. Specifically, we can help you:
01Advance Disease Research: By enabling RNA delivery into non-liver tissues, our platform provides a tool for dissecting disease mechanisms in the spleen, lung, skin, and immune system.
02Accelerate Preclinical Development: Our validated LNP formulations streamline the design and testing of RNA therapeutics, reducing barriers to proof-of-concept studies.
03Expand Therapeutic Applications: From genetic lung diseases to skin disorders and immune-based therapies, our platform empowers researchers to explore new frontiers in RNA medicine.
04Enable Next-Generation Therapies: With the ability to deliver diverse RNA modalities, including gene editing tools, our platform supports the creation of transformative therapeutic solutions.
By partnering with us, you gain access to a robust, patent-protected LNP technology platform that has already proven its effectiveness in multiple in vivo applications. Whether your goal is to advance basic research, develop novel therapeutics, or translates RNA technologies into clinical practice, our extrahepatic delivery expertise provides the tools and support needed to succeed.
Reference
- Song D., et al. Tuning lipid nanoparticles for RNA delivery to extrahepatic organs[J]. Advanced Materials, 2024, 36(44): 2401445.
Our products and services are for research use only and cannot be used for any clinical purposes.
