<p>The current study aimed to address the challenge of poor solubility, a significant concern in the pharmaceutical industry, affecting approximately 40% of marketed drugs and 70–90% of newly developed therapeutic agents, by developing nanogels as a drug delivery system using poorly soluble olanzapine (OZP) as a model drug. Nanogels were synthesized using a modified free-radical polymerization technique, crosslinking poloxamer-407 (P-407) and 2-acrylamido-2-methylpropane sulfonic acid (AMPS) with N, N’-methylene-bis-acrylamide (MBA). Characterization confirmed the successful formation of nanogels, with zeta-sizer analysis indicating a particle size of 161 ± 13&#xa0;nm. Scanning electron microscopy (SEM) images revealed a highly porous structure with an irregular surface topology, facilitating water penetration and drug release. Fourier transform infrared spectroscopy (FTIR) analysis confirmed the structural integrity and drug incorporation. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) suggested that OZP remained thermally compatible within the amorphous nanogel system. X-ray diffraction (XRD) analysis revealed the amorphous nature of the nanogel matrix, supporting improved drug solubility. A gel fraction of 84.2% suggested efficient crosslinking and a stable polymeric network. Swelling occurred within 5&#xa0;min, and in vitro release studies showed rapid drug release within 5–10&#xa0;min under both pH 1.2 and 6.8 conditions. Notably, the solubility of OZP increased by 37.7-fold. Additionally, acute oral toxicity studies confirmed their biocompatibility, and a stability study indicated that the nanogels remained stable for 6 months. These findings demonstrate that P-407/poly(AMPS) nanogels represent a promising platform for improving the solubility and in vitro release performance of poorly soluble drugs.</p> Graphical abstract <p></p>