Tumors are considered dangerous due to their significant global mortality rate, with breast cancer (BC) being a major contributor to this statistic, impacting almost all tumor patients worldwide. Conventional methods for BC treatment, such as special naringin (NG) chemotherapy based on nanotechnology components, have been insufficient, and a new approach has been used to improve drug delivery (DD) to cancer. Herein, developed biocompatible nanoparticles (NPs) comprising NG-loaded zinc metal-organic framework-5 (NG-MOF-5) encapsulated with liponiosomes (LNs) to create NG-MOF-5@LNs. Various biophysical characteristics of free NG, MOF-5, and NG-MOF-5@LNs NPs were studied, including XRD, FTIR, TEM, SEM, zeta potential (ZP), hydrodynamic size, PDI, loading efficiency (LE), encapsulation efficiency (EE), drug release (DR), and drug-release kinetics. TEM images showed that NG-MOF-5@LNs NPs consisted of monodispersed spherical-like particles with average diameters of 122.5 nm (*P < 0.05). The optimized NG-MOF-5@LNs exhibited a particle size (PDI: 139.8 nm) and a ZP (+ 21 mV). The EE and LE for NG-MOF-5@LNs were 89.15% and 14.05%, respectively. Four kinetic models were examined to understand the NG release mechanism at pH 6.9, with the Higuchi model indicating excellent fit (R2 = 0.9988). The MTT cell viability assay demonstrated anti-cancer activity against MCF-7 BC cells, with inhibitory concentrations (IC50) of 231.9, 188.2, and 21.6 µg/mL (*P < 0.05) for MOF-5, NG, and NG-MOF-5@LNs, respectively, indicating an apoptosis effect on MCF-7 cells. NG-MOF-5@LNs is expected to emerge as a novel long-term-release anticancer agent. NG-MOF-5@LNs may represent a superior option for BC therapy compared to conventional NG formulations.