Lymphoid and CXCR4 Cell Targeted Lipid Nanoparticles Facilitate HIV-1 Proviral DNA Excision

Advancements in antiretroviral therapy (ART) enable those living with the human immunodeficiency virus type one (HIV-1) to lead longer, healthier lives free from disease comorbidities. However, lifelong ART poses challenges. These include social stigma, medication costs, drug accessibility, mental health, and drug-related toxicities. Moreover, ART does not eliminate latent HIV-1 DNA. Viral persistence in tissue and cell reservoirs results in viral rebound after ART interruption. New strategies are required to achieve a functional HIV-1 cure. To excise latent HIV-1, C-X-C motif chemokine receptor 4 (CXCR4) ligand-decorated lymphoid tissue-targeting lipid nanoparticles (LNPs) for CRISPR-Cas9/gRNA delivery are developed. These LNPs enhance mRNA translation and demonstrate CXCR4-mediated improved uptake to eliminate HIV-1 DNA in infected CD4+ T cells. LNPs also facilitate targeted drug delivery, achieving HIV-1 DNA excision in ART-treated, infected humanized mice. This study emphasizes the potential of tissue and cell-targeted LNPs for effective HIV-1 DNA excision.