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Abstract Background Nanoparticle-based drugs are new inventions in the management of the Human immunodeficiency virus (HIV) pandemic, especially resistant forms of the virus in anatomical sanctuary sites and organs such as the testis. However, safety issues must be resolved to attain the optimal potential of newer nano-drug formulations. Aim The study investigated the toxicological potential of synthesized Tenofovir Nanoparticles (TDF-N) on testicular indices when used for the prevention and treatment of HIV. Methodology Fifteen male Sprague–Dawley (SD) rats with weight ranging from 230 g to 250 g were randomly assigned into groups A (control, saline), B (TDF), and C (TDF-N). The testes were removed for sperm analysis and processed for H/E and PAS stains. Cell counts and cellular measurements; the diameter and the area of the testicular seminiferous tubules were measured using ImageJ and Leica software 2.0. Results A significant reduction (p

Introduction: Nanoparticle drug delivery system has the potential to minimize the adverse effects, difficulties in biological barrier penetration, therapeutic adherence, and multiple pill administration of current HIV management therapy. This study aimed to prepare tenofovir disoproxil fumarate (TDF) loaded silver nanoparticles (AgNPs) as a potential nano-drug. Methods: The AgNPs were prepared using the chemical reduction method and conjugated with TDF. TDF-AgNPs were characterized using spectroscopic and microscopic techniques to determine the nanoparticles' size, morphology, elemental compositions, and drug release. Results: Ultraviolet-visible spectroscopy showed absorption peaks between 250–328 nm for all four TDF-AgNPs. Fourier-transform infrared (FTIR) spectroscopy confirmed the conjugation of TDF to AgNPs with the presence of C-N and O-H functional groups on TDF-AgNPs. The microscopic images revealed hexagonal (0.5 M, 1.5 M) and spherical (1 M, 2 M) TDF-AgNPs with a mean particle size from 7 nm to 22 nm. Energy-dispersive X-ray (E552DX) spectroscopy established the presence of silver in the nano-conjugate. In addition, the drug release profile of the TDF-AgNPs showed maximum release at the highest time interval (60 min) using phosphate buffer saline as a solvent medium at physiological pH 7.4. Conclusion: This study demonstrates the successful preparation of small to medium-sized, majorly monodispersed AgNPs using a chemical reduction method and their successful conjugation to TDF. This is the first study on the preparation of TDF-AgNPs for possible management of HIV-1 infection.