Cleavable disulfide bonds are extremely valuable functional groups for numerous biological applications, including applications as antitumor treatments, gene delivery, and diagnosis. Herein, we demonstrate the use of dimethyl 3,3′-dithiobispropionimidate (DTBP) as a disulfide cleavable bond based cross-linker in nano-composites that encapsulate and release nucleic acids in sample preparation systems for disease diagnoses. We conjugated DTBP with nano-composites, such as amine group-modified diatomaceous earth (DA), which is a solid substrate, and a zinc oxide nanomultigonal shuttle (ZnO NMS) that disrupts cell membranes without chaotropic detergents and improved the quantity and purity of nucleic acids from various biological samples. After encapsulating nucleic acids, the cleavable disulfide bond of DTBP was used to release nucleic acids by breaking disulfide bonds using dithiothreitol (DTT), resulting in highly enhanced efficiency of downstream analyses without PCR inhibitors such as high salt concentrations and SDS. Therefore, nano-composites with cleavable disulfide linkages have potential for various biological applications, including disease diagnostics and therapies.