Next-Generation Vaccine: One That Knows Its Target

Authored by: Sicheng Chen

Art by: Vanessa Chen Hsieh

Although the COVID-19 pandemic has subsided, many people still have lingering questions about the mRNA-based COVID-19 vaccines: How do they confer immunity? Where do they go once inside our bodies? While the first question has been widely discussed, the second is often overlooked. For many, it remains unclear how the mRNA is packaged and delivered—a process that lies at the heart of how these vaccines work.

Understanding the answer to this second question would offer us a glimpse into what scientists today are striving to achieve in vaccine design: creating vaccines that can reach the right target. In fact, the vector that delivers mRNA in current COVID-19 vaccines— lipid nanoparticle (LNP) — has become the foundation for this new direction. In this article, we’ll explore how the LNPs found in the COVID-19 vaccine are paving the way for the next generation of vaccines.

Before we discuss how LNPs are transforming vaccine design, it’s worth first understanding how traditional vaccines work. Traditional vaccines generally contain antigens—either inactivated or attenuated pathogens, purified proteins, or polysaccharide components—that stimulate the immune system to recognize and remember the corresponding infectious agent. After administration, these antigens are taken up by antigen-presenting cells (APCs) at the injection site, which then migrate to draining lymph nodes to activate B and T lymphocytes, which in turn initiate adaptive immune protection [1].

Structurally, traditional vaccines are comparable to everyday drugs: they may consist of free, unencapsulated antigens or antigenic cargo enclosed within a delivery vector, much like tablets or capsule-coated drugs. Take the COVID-19 mRNA vaccine as an example — the LNP essentially serves as a capsule-like coating that protects the mRNA and facilitates its entry into host cells. However, despite their promising therapeutic effect, the COVID-19 vaccine, as well as many other conventional  vaccines, lack the vector that enables active targeting to specific tissues. In fact, most vaccines today either get expressed locally at site of administration, or get circulated in the blood and ultimately taken up by the liver, with very little absorption in target tissues or cell types [2].

This limitation makes targeting a crucial next step in vaccine development. Inspired by the LNPs used in the COVID-19 vaccines developed by Moderna and Pfizer, many researchers are now engineering LNPs with targeting ligands and surface modifications to enable precise delivery to desired tissues or immune-cell populations in future vaccines and nucleic-acid therapeutics [3].

To understand how researchers tune LNP targeting, it helps to first look at how these nanoparticles are made. Similar to those used in the COVID-19 vaccines, LNPs are generally composed of four key lipids: ionizable cationic lipids, phospholipids, cholesterol, and polyethylene glycol (PEG)–conjugated lipids [4]. Because lipids are soluble in ethanol, researchers first prepare a cocktail of these lipids in an ethanolic solution following specific ratios. This lipid mixture is then rapidly combined with an aqueous solution containing the nucleic acid cargo. Upon mixing with the aqueous solution, the slightly acidic environment will protonate ionizable cationic lipids, which then promote electrostatic bonding with the negatively charged nucleic acids. Meanwhile, hydrophobic interactions among the nonpolar lipid tails would drive the formation of a spherical nanoparticle, spontaneously encapsulating the genetic material within the lipid cocktail, namely LNP[5]. 

After LNP is formed, the next question arises: how to engineer it so it knows which organ or cell to go to? In the COVID-19 LNP vaccines, which lack organ- or cell- tropism, the nanoparticles are primarily endocytosed at the site of administration. However, recent advances such as the Selective Organ Targeting (SORT) strategy have enabled scientists to direct LNPs to specific organs by incorporating a fifth lipid component into the formulation of LNP [6]. Experimentally, this fifth lipid can be added by mixing with the four other primary lipids in LNP. In essence, this strategy modifies the overall surface charge and chemical composition of the nanoparticle, which in turn influences how LNP interacts with serum proteins, immune cells, and endothelial surfaces in different tissues.

One canonical demonstration of SORT is from Cheng et al. 's research on “Selective Organ Targeting (SORT) nanoparticles for tissue-specific mRNA delivery” (Nature Nanotechnology, 2020). In that work, the authors added DOTAP, a permanently cationic lipid, as a SORT molecule to standard LNP formulations. As the DOTAP molar fraction increased, the predominant site of mRNA expression shifted from the liver to the spleen and then to the lungs, showing that organ tropism could be controlled by tuning lipid composition [7]. Leveraging this strategy, researchers can generate LNPs with other tissue tropisms by introducing a different combination of lipids during LNP synthesis. Consequently, that modifies the LNP’s surface charge and other properties, which in turn affects which plasma proteins can bind to the nanoparticle. As a result, the LNP’s uptake is redirected toward specific cell populations and tissues.

In summary, recent advances have highlighted both the promise and the remaining challenges of LNP-based vaccine delivery. Although the success of COVID-19 vaccines demonstrated the power of LNPs, achieving precise organ targeting remains a key hurdle due to potential off-target effects such as hepatic injury [8]. Nevertheless, targeting strategies like SORT mark major progress toward safer and more effective vaccines, paving the way for organ- and cell-specific therapeutics.

Reference:

1. UChicago Medicine. “How Do Vaccines Work?” www.uchicago medicine.org, 4 Dec. 2020,www.uchicagomedicine.org/forefront/coronavirus-disease-covid-19/demystifying-vaccines-1.

2. Parrett, Brian J., et al. “Reducing Off-Target Expression of MRNA Therapeutics and Vaccines in the Liver with MicroRNA Binding Sites.” Molecular Therapy Methods & Clinical Development, vol. 33, no. 1, Mar. 2025, p. 101402, https://doi.org/10.1016/j.omtm.2024.101402.

3. HUANG, Xiaonan, et al. “Unlocking the Therapeutic Applicability of LNP-MRNA: Chemistry, Formulation, and Clinical Strategies.” Research, 12 Apr. 2024, https://doi.org/10.34133/research.0370.

4. Godbout, Kelly, and Jacques P. Tremblay. “Delivery of RNAs to Specific Organs by Lipid Nanoparticles for Gene Therapy.” Pharmaceutics, vol. 14, no. 10, 7 Oct. 2022, p. 2129, https://doi.org/10.3390/pharmaceutics14102129.

5. “A Complete Guide to Understanding Lipid Nanoparticles (LNP).” Inside Therapeutics, 10 Sept. 2025, insidetx.com/resources/reviews/complete-guide-to-understanding-lipid-nanoparticles-lnp/

6. Wang, Xu, et al. “Preparation of Selective Organ-Targeting (SORT) Lipid Nanoparticles (LNPs) Using Multiple Technical Methods for Tissue-Specific MRNA Delivery.” Nature Protocols, 31 Oct. 2022, https://doi.org/10.1038/s41596-022-00755-x.

7. Cheng, Qiang, et al. “Selective Organ Targeting (SORT) Nanoparticles for Tissue-Specific MRNA Delivery and CRISPR–Cas Gene Editing.” Nature Nanotechnology, vol. 15, no. 4, 1 Apr. 2020, pp. 313–320, www.nature.com/articles/s41565-020-0669-6, https://doi.org/10.1038/s41565-020-0669-6.

8. Chen, Jingan, et al. “Combinatorial Design of Ionizable Lipid Nanoparticles for Muscle-Selective MRNA Delivery with Minimized Off-Target Effects.” Proceedings of the National Academy of Sciences of the United States of America, vol. 120, no. 50, 7 Dec. 2023, https://doi.org/10.1073/pnas.2309472120.