A hierarchical nanocomposite of 10-hydroxycamptothecin (HCPT), a nonionic and lipophilic anticancer agent, intercalated layered zinc hydroxide nitrate (LZH) encapsulated in liposomes was fabricated. HCPT molecules were incorporated into sodium cholate (Ch) micelles, and the resulting negatively charged HCPT-loaded Ch micelles were then introduced into the LZH galleries to form an HCPT/Ch intercalated LZH (designated HCPT-Ch-LZH) host-guest nanohybrid. The nanohybrid particles were then coated with liposomes (LSs), resulting in the formation of a core-shell nanocomposite denoted as (HCPT-Ch-LZH)@LS. Using XRD, FT-IR, SEM, TEM, DLS, and elemental analyses, the obtained samples were characterized. Particular attention was paid to the effect of liposome-coating on the HCPT-Ch-LZH's water solubility and drug release. The results demonstrate that the nanocomposite has superior water dispersity and enhanced drug sustained-release performance compared to HCPT-Ch-LZH, indicating that the liposome-coating of drug-LZH nanohybrids is an effective strategy for improving their water dispersity and sustained-release performances. This study presents an efficient strategy for constructing LZH-based drug delivery systems for nonionic and lipophilic medicines.