Abstract

Antiretroviral therapy (ART) had transformed HIV infection into a chronic, manageable condition. However, drug 
resistance, poor adherence, and limited drug penetration into viral reservoirs hinder long-term viral suppression 
and complicate cure strategies. Novel drug delivery systems are urgently needed to address these limitations. 
Nanoparticle-based platforms, which can encapsulate, protect, and release antiretroviral agents in a controlled 
manner, represent a promising solution. This review evaluated nanoparticle-mediated delivery strategies for 
antiretroviral drugs, focusing on their potential to overcome resistance mechanisms, enhance pharmacokinetics, and 
improve patient outcomes. This review synthesized peer-reviewed studies from PubMed, Scopus, and Web of Science 
(2010–2025), focusing on in vitro, in vivo, pharmacokinetic, and early-phase clinical reports of nanoparticle
formulated antiretroviral drugs. Lipid nanoparticles, polymeric nanocarriers, and inorganic nanoparticles improved 
drug solubility, extend plasma half-life, and enhanced biodistribution to sanctuary sites such as lymph nodes and the 
central nervous system. Long-acting nanosuspensions of cabotegravir and rilpivirine maintain therapeutic 
concentrations for up to eight weeks, improving adherence. Polymeric nanoparticles and nanogels enable co-delivery 
of multiple drugs, reducing viral escape. Preclinical studies showed up to 10-fold increases in intracellular drug 
concentrations and 2–3 log10 reductions in viral replication compared to free drugs. Safety remained favorable, 
though immunotoxicity and large-scale manufacturing challenges persist. Nanoparticle-based antiretroviral 
delivery represented a frontier in HIV management, addressing adherence, resistance, and drug distribution 
challenges. Translational efforts should focus on optimizing formulations, ensuring affordability, and tailoring 
delivery systems to resource-limited settings. 
Keywords: HIV, Nanoparticles, Antiretroviral therapy, Drug resistance, Drug delivery.