Book excerpt: HIV/AIDS still continues to be a pandemic and global emergency and is a leading cause of death among the women of reproductive age (15-49 yr). Women are more vulnerable for HIV infection due to anatomical and physiological features of female reproductive system. Various efforts are being explored to develop new HIV prevention technologies which could be particularly beneficial for women, such as cervical barriers and microbicides. Microbicides are anti-infective medication formulated for topical self-administration before intercourse to protect against HIV and other sexually transmitted pathogens presents potential intervention strategy. Topical administration of microbicides was found to be clinically effective in reducing the overall risk of HIV infection among high-risk women. One of the FDA approved microbicides, Tenofovir has shown efficacy in suppression of viral replication and exerted no safety concerns towards renal toxicity but low absorption from gel formulation is a concern. Formulations based on combination of microbicides was found to be more effective than formulations based on single microbicide. A primary focus of this dissertation research project is to design and develop a vaginal delivery system for combination of microbicides that can sustain the acidic environment of the vaginal cavity and able to release the loaded microbicides as response to change in pH. Microbicide loaded nanoparticles were prepared from Eudragit-S-100, incorporated with Tenofovir and Etravirine. The nanoparticles protected the encapsulated drugs and released the drugs as response to change in pH. The nanoparticles encapsulated two microbicides with different solubility profile without any cytotoxicity. Though, the nanoparticles were able to encapsulate the drug and release in simulated environment in a pH sensitive manner, encounters next challenge of mucosal layer which traps and limits the exposure of foreign particles. The later part of this dissertation project was to develop Dapivirine loaded mucus penetrating pH sensitive nanoparticles surface engineered with low molecular weight poly ethylene glycol. The aim of this work was to enhance the number of NPs reaching epithelia cells after crossing the physical barrier of mucosal layer. These surface modified nanoparticles were characterized for particle size distribution, morphology, drug loading. Cellular uptake profiles of mucus penetrating ES-100 nanoparticles was studied in human vaginal epithelial cells (VK2 E6/E7) using confocal microscopy. Cytotoxicity profile was studied using cell viability assays.