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.