Are you currently facing challenges in achieving precise and efficient drug delivery? Does off-target toxicity and limited therapeutic efficacy hinder your biopharmaceutical projects? Our Selective Organ Targeting (SORT) LNP Development service at Creative Biolabs helps you overcome these hurdles by enabling highly specific and potent delivery of your therapeutic payloads to the desired organs. We achieve this through our innovative approach to designing and optimizing lipid nanoparticles (LNPs), ensuring your agents reach their targets with unprecedented precision.

Selective Organ Targeting (SORT) LNP Development

Selective Organ Targeting (SORT) Lipid Nanoparticle (LNP) Development is an advanced method for targeted drug delivery that uses engineered nanoparticles to direct therapeutic payloads to specific organs. Unlike traditional LNPs, which are often limited to liver delivery, SORT technology allows for precise control over biodistribution. The foundation of this technology lies in the ability to modify the LNP's surface to alter its interaction with plasma proteins. The LNPs are typically composed of four key components: an ionizable cationic lipid, a helper lipid, cholesterol, and a PEGylated lipid. This structure provides a stable and biocompatible vehicle for delivering various nucleic acid-based therapeutics, including mRNA, siRNA, and gene-editing complexes.

Fig.1 SORT LNP formulation and targeted delivery.

Our SORT LNP Development Solution

Our SORT LNP Solution at Creative Biolabs provides a systematic approach to developing lipid nanoparticles with a high degree of organ specificity. We leverage the principle that small changes in the LNP's composition can lead to significant changes in its biodistribution.

• Commonly Used SORT Molecules: Core SORT constituents frequently comprise ionizable lipids, including DLin-MC3-DMA (MC3) for hepatic targeting, alongside permanently charged cationic or anionic lipids such as DOTAP or 18PA that reroute LNPs toward splenic or pulmonary sites.
• Classification of SORT LNPs:
  SORT LNPs can be classified based on their targeting mechanism, which is determined by the specific SORT molecule incorporated into the lipid nanoparticle. This modification dictates how the LNP interacts with plasma proteins and, consequently, which organs it will accumulate in.

  Fig.2 Selective organ targeting (SORT) technology achieves liver- and lung-specific mRNA delivery.^1,3

  • Liver-Targeting LNPs: These are the most common type of LNPs. They are designed to mimic very-low-density lipoprotein (VLDL), which naturally targets the liver. Their surface properties, often including a pKa in the slightly acidic to neutral range, facilitate binding to apolipoprotein E (ApoE) in the bloodstream. ApoE then serves as a ligand, guiding the LNP to low-density lipoprotein receptors (LDLR) on liver cells (hepatocytes), where they are taken up through endocytosis.
  • Spleen/Lung-Targeting LNPs: These nanoparticles are specifically engineered to avoid the liver and target other organs. This is achieved by adjusting the LNP's composition to change its affinity for plasma proteins. For example, incorporating a permanently cationic or anionic lipid as the SORT molecule alters the LNP's surface charge and properties. This shifts the protein corona from ApoE to other proteins, such as β2-glycoprotein I (β2-GPI). The interaction with β2-GPI or other yet-to-be-identified proteins then mediates the LNP's uptake by cells in the spleen and lungs, allowing for targeted delivery to these tissues.
  • Other Organ-Targeting LNPs: While liver, spleen, and lung targeting are the most established, research is ongoing to expand SORT to other organs. For example, the incorporation of specific targeting ligands, such as antibodies or peptides, on the LNP surface can facilitate delivery to a wider range of tissues, including the brain, heart, or tumors. These ligands recognize and bind to unique receptors or markers on the surface of the target cells, enabling highly specific delivery. This approach is key to developing therapies for diseases that are not treatable by targeting the liver, spleen, or lungs.
• Targeting Mechanisms: The primary mechanism involves modulating the pKa of the ionizable lipid. At acidic pH within the endosome, the ionizable lipids become positively charged, enabling them to disrupt the endosomal membrane and release their cargo into the cytoplasm. By carefully adjusting the pKa and surface charge, we can control the LNP's interaction with plasma proteins, thus dictating its ultimate destination within the body.

Application

The applications of targeted drug delivery are vast and continue to expand with the advancement of technologies like SORT. These implementations prove transformative in therapeutic contexts where off-target actions pose significant risks.

• Genetic Disorders: Delivery of therapeutic mRNA to specific organs can correct deficiencies in protein expression, as seen in diseases like tyrosinemia and transthyretin amyloidosis.
• Gene Editing: The precise delivery of gene-editing components to affected tissues allows for targeted gene correction, offering new hope for Duchenne muscular dystrophy and other genetic diseases.
• Cancer Therapy: Targeted delivery of immunomodulatory agents or cytotoxic drugs to tumor cells can enhance efficacy while sparing healthy tissue.
• Infectious Diseases: LNPs can deliver mRNA vaccines to immune cells, stimulating a robust immune response against pathogens.

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What We Can Offer?

Creative Biolabs is uniquely positioned at the forefront of targeted drug delivery innovation. Our team of expert biologists, chemists, and engineers brings over two decades of collective experience in developing sophisticated delivery solutions. We provide an integrated portfolio of solutions to advance your scientific investigations:

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Why Choose Us?

Partnering with Creative Biolabs means choosing a path to accelerated drug development, enhanced therapeutic efficacy, and a significant reduction in off-target effects. Our commitment to innovation and scientific excellence ensures that your therapeutic agents reach target area with unprecedented precision, unlocking new possibilities for disease treatment.

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Published Data

Fig.3 sPD-L1 mRNA expression in vitro and biophysical profiling mRNA-MC3-LNPs and mRNA-DOTAP-LNPs.^2,3

The study titled "Engineered Lipid Nanoparticles for Liver- and Spleen-Specific Delivery of Ribonucleoproteins" provides a compelling demonstration of the principles behind SORT. The researchers successfully developed a methodology to produce LNPs capable of delivering a ribonucleoprotein (RNP) complex to the liver and spleen. The experiment involved creating a library of ionizable lipids with a focus on modulating the pKa and overall charge of the LNPs. The researchers systematically varied the lipid composition and the molar ratio of the ionizable lipid, which is a core component of the LNP, to control the biodistribution. They found that by adjusting these parameters, they could significantly alter the delivery profile of the RNPs. For instance, LNPs with a high pKa were found to preferentially accumulate in the liver, while those with a lower pKa were redirected to the spleen. The results showed that these engineered LNPs effectively delivered the RNP to the intended organs, leading to successful gene editing as confirmed by in vivo experiments. The study's conclusion highlights that this rational design strategy for LNPs is a powerful tool for achieving tissue-specific delivery of therapeutic payloads, thus supporting the core tenets of Selective Organ Targeting.

FAQs

Creative Biolabs offers a comprehensive suite of services for Selective Organ Targeting (SORT) LNP Development, designed to support your journey from concept to clinical validation. Our expertise, innovative technologies, and commitment to quality ensure that your therapeutic agents reach their intended targets with precision.

Connect with our experts for project-specific consultation and detailed insights.

References

1. Liu, Yaping et al. "Development of mRNA Lipid Nanoparticles: Targeting and Therapeutic Aspects." International journal of molecular sciences vol. 25,18 10166. 22 Sep. 2024, https://doi.org/10.3390/ijms251810166
2. Sun, Han et al. "Application of Lung-Targeted Lipid Nanoparticle-delivered mRNA of soluble PD-L1 via SORT Technology in Acute Respiratory Distress Syndrome." Theranostics vol. 13,14 4974-4992. 4 Sep. 2023, https://doi.org/10.7150/thno.86466
3. Distributed under Open Access license CC BY 4.0, without modification.

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