Polypropylene sulfide (PPS) as reactive oxygen species (ROS) responsive nanoparticles (NPs) have attained great interest for drug delivery applications in many diseases such as cancer, pulmonary, neurovascular, cardiovascular, and age-related diseases. Despite great potential of PPS NPs as a nanocarrier, it remains relatively less explored for small molecules (drug) delivery, as the current method of PPS NPs synthesis involving strong bases like sodium methoxide (NaOMe) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) results in breakdown of base sensitive drugs or molecules. Herein, we are reporting a facile synthesis method for PPS NPs preparation with high drug loading capacity (five times higher than the reported synthesis method) of base-sensitive cargos (Paclitaxel/Dil dye) within the PPS matrix and protection from possible breakdown of drug during synthesis. The NPs prepared via our method possess oxidative-responsive release of drug, preservation of drug bioactivity, and excellent storage stability at room temperature or 4°C. PPS NPs system demonstrate biocompatibility and drug-loaded NPs provide efficient anticancer activity against breast cancer cells. Our method of PPS NPs synthesis is suitable to prepare a delivery system with higher loading capacity of drug and small molecules for different biomedical applications. © 2021 Wiley Periodicals LLC.