Abstract <p>HIV remains a major global health challenge with antiretroviral therapy (ART) effectively suppressing viral replication. However traditional ART does not eliminate viral reservoirs and is limited by systemic toxicity, long-term adherence burdens, and incomplete tissue penetration. These limitations highlight an important scientific problem in the inability of conventional ART to achieve durable remission or cure. Nanoparticle-mediated drug delivery systems have emerged as a transformative approach to address these limitations by improving drug solubility, stability, and targeted delivery to infected cells and viral sanctuaries such as the brain, lymphoid organs, and gastrointestinal mucosa. Different nanocarrier platforms including liposomes, polymeric nanoparticles, dendrimers, and lipid-based vesicles enable both passive and active targeting strategies. Functionalization with ligands such as antibodies, peptides, aptamers, and sugar moieties enhance cellular uptake, reduces off-target effects, and optimizes pharmacokinetics and biodistribution. Controlled-release formulations extend drug half-life and reduce dosing frequency, supporting long-acting regimens. Beyond drug delivery, nanoparticles also facilitate immunomodulatory therapies, therapeutic vaccines, and advanced gene-editing technologies such as CRISPR–Cas9. The convergence of nanotechnology, mRNA platforms, and artificial intelligence-driven drug development represents a paradigm shift toward individualized and precision HIV treatment. Despite these advances, significant translational challenges remain, including nanotoxicity, long-term safety, large-scale GMP manufacturing, regulatory barriers, and cost-effectiveness. Addressing these barriers is essential to unlock the full potential of nanoparticle-based strategies and translate them into equitable and sustainable clinical solutions.</p> Graphical abstract <p></p>