This study was designed to develop buffered thermoreversible gel containing tenofovir (TNF) loaded PLGA nanoparticles for sustained drug release and prolonged protection from HIV-1 sexual transmission. Optimized buffered thermoreversible formulation containing TNF loaded PLGA nanoparticles was in solution form at 2-8oC and converted into a gel matrix at 28oC. PLGA nanoparticles were prepared by two methods; (a) Solvent diffusion method, (b) Emulsification- solvent evaporation and effective particles diameter was 94.3-228 nm and 265-413 nm respectively by dynamic light scattering technique. Morphology of the particles was analyzed by scanning electron microscope and micro image showed smooth & spherical in shape nanoparticles. Triton® X-100 a non-ionic surfactant effectively reduced the particle size of nanoparticles in solvent diffusion method but the desired TNF encapsulation was not observed. Drug encapsulation and drug loading were analyzed in nanoparticles prepared by emulsification-solvent evaporation and the values were 1.43-10.78% and 0.25-1.18% respectively. In-vitro release of TNF from Buffered thermoreversible gel containing PLGA nanoparticles was conducted in simulated vaginal fluid (pH 4.2). In 8 h, cumulative % drug release was 61% and after 24 h it was 67.75%. Drug release mechanism was diffusion and erosion controlled. Results demonstrated the therapeutic potential of the vaginal nano gel formulation for prolonged protection against HIV-1 transmission as an STD.