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Herein, we report highly porous and amorphous nanomatrices developed by cross-linking polymerization with subsequent condensation technique for solubility, dissolution and ultimately bioavailability enhancement of poorly soluble drug olanzapine (OLN). β-cyclodextrin was chemically cross-linked with monomer 2-acrylamido 2-methylpropane sulfonic acid (AMPS) by using methylene bis acrylamide (MBA) as cross-linking agent. Developed nanomatrices were characterized by zetasizer, FTIR, XRD, SEM, DSC, swelling, sol-gel, drug loading, stability, porosity (%), solubility, and in-vitro dissolution analysis. The developed porous nanomatrices are intended for oral administration of poorly soluble drugs therefore, to determine the biocompatibility of the system to the biological environment, in-vivo cytotoxicity study was also conducted using rabbit model which endorsed the safety of the nanomatrices with biological …