mRNA Lipid Nanoparticles Make It Impossible for The "Hidden Enemy" of AIDS to Escape

In the fight against AIDS, scientists have always been committed to finding a way to completely cure this stubborn disease. In recent years, the rapid development of mRNA technology has brought unprecedented opportunities to the field of gene therapy. From the successful development of COVID-19 vaccines to the clinical application of CRISPR gene editing technology, mRNA technology has continuously refreshed our understanding of life sciences.

Today, a new study aimed at reversing HIV latency has once again brought this field to the forefront. Imagine if the HIV virus lurking in resting T cells could be accurately "awakened" to eliminate these "latent enemies" in one fell swoop, then the true cure for AIDS may not be far away.

Recently, in a research report entitled "Efficient mRNA delivery to resting T cells to reverse HIV latency" published in the international journal Nature Communications, scientists from the University of Melbourne and other institutions explored how mRNA lipid nanoparticles (LNPs) can become a new hope for reversing HIV latency. The latent state of HIV virus is the biggest obstacle to the cure of AIDS. Although traditional antiretroviral therapy (ART) can effectively inhibit viral replication, it cannot eliminate the latent viral reservoir. Therefore, finding a new strategy to activate HIV latent transcription and then eliminate infected cells has become a research focus.

In this study, researchers developed an efficient mRNA-LNP delivery system that can deliver mRNA that reverses HIV latency to resting T cells, thus providing new possibilities for the cure of AIDS. In the article, the researchers used resting CD4⁺ T cells as the main experimental subjects, which are the main hosts of HIV latency. They used an innovative LNP formula (LNP X) composed of SM-102 ionic lipids and β-sitosterol, which has unprecedented transfection efficiency.

Figure 1. LNP X formulation potently transfects primary CD4⁺ T cells in the absence of pre-stimulation. (Cevaal, Paula M., et al., 2025)

Development of innovative delivery system

First, the research team optimized the composition of lipid nanoparticles (LNPs). They replaced the ionized lipid DLin-MC3-DMA in the traditional patisiran LNP with SM-102 and introduced the natural cholesterol analog β-sitosterol to develop LNP X. This novel lipid combination significantly enhanced the delivery efficiency of mRNA while reducing cytotoxicity. Experimental results showed that LNP X had a transfection efficiency of 76% in resting CD4⁺ T cells without pre-stimulation, which was much higher than the 2.1% of traditional patisiran LNP. In addition, the transfection efficiency of LNP X in stimulated CD4⁺ T cells reached more than 75%, achieving efficient transfection even at low doses.

Experimental verification of reversing HIV latency

The researchers encapsulated mRNA encoding HIV Tat protein in LNP X to verify its ability to activate HIV transcription. Tat protein is a key regulator of HIV transcription and can promote the synthesis of viral RNA. The experimental results showed that the expression of HIV-related genes in CD4⁺ T cells treated with Tat-LNP X was significantly increased, including HIV RNA transcripts at various stages such as transcription initiation, elongation, completion and splicing. This effect was not observed in the control group mCherry-LNP X. In addition, Tat-LNP X can also induce the release of HIV virus particles, indicating that it can effectively reverse the latent state of HIV.

Delivery potential of CRISPR activation system

In addition to Tat protein mRNA, the researchers also used LNP X to encapsulate and deliver the CRISPR activation system (CRISPRa). The CRISPRa system is composed of a catalytically inactive Cas9 protein (dCas9) fused to a transcriptional activation domain, which can specifically activate transcription in the HIV promoter region. The experimental results showed that LNP X can successfully deliver the CRISPRa system and induce the expression of HIV-related genes in CD4⁺ T cells. As expected, the expression of HIV RNA in cells treated with CRISPRa-LNP X increased significantly, while the scramble CRISPRa-LNP X in the control group did not have this effect.

Limitations of the study and future prospects

Although LNP X has shown great potential in reversing HIV latency, the study also has some limitations. For example, although a single dose of Tat-LNP X can significantly enhance HIV transcription, it does not lead to virus-mediated cytotoxicity or immune-mediated clearance. This suggests that other interventions may need to be combined to enhance the sensitivity of infected cells to death or promote their clearance. In addition, the immunogenicity, biodistribution and half-life of LNP X in vivo still need to be further explored to determine the optimal therapeutic dose and safety.

In summary, this study provides a new strategy for reversing HIV latency by developing an efficient mRNA-LNP delivery system (LNP X). LNP X can not only efficiently deliver therapeutic mRNA to resting CD4⁺ T cells, but also show great potential in complex RNA delivery. In the future, as scientists further study and optimize LNP X, we have reason to believe that this technology is expected to bring new breakthroughs in the cure of AIDS, leaving the "latent enemy" nowhere to escape.