Introduction Cancers are regarded as hazardous due to their high worldwide death rate, with breast cancer (BC), which affects practically all cancer patients globally, playing a significant role in this statistic. The therapeutic approach for BC has not advanced using standard techniques, such as specialized naringin (NG) chemotherapy. Instead, a novel strategy has been utilized to enhance smart drug delivery (SDD) to tumors. Significance: Herein, we established NG-loaded zinc metal-organic framework-5 (NG-MOF-5) coated with liponiosomes (LNs) to manufacture NG-MOF-5@LNs nanoparticles (NPs) for antibacterial and cancer treatment. Methods MOF-5, NG, and NG-MOF-5@LNs were evaluated with XRD, TGA, FTIR, SEM, TEM, PDI, ZP, encapsulation efficiency (EE), loading efficiency (LE), and drug-release (DR) kinetics. We examined the antibacterial activity involving minimum inhibitory concentration (MIC) and zone of inhibition by NG, MOF-5, and NG-MOF-5@LNs. The cell viability, necrosis, and total apoptosis (late and early) were evaluated for anti-cancer activity against MCF-7 BC cells. Results TEM results demonstrated that NG-MOF-5@LNs formed monodispersed spherical-like particles with a size of 122.5nm, PDI of 0.139, and ZP of +21mV. The anti-microbial activity results indicated that NG-MOF-5@LNs exhibited potent antibacterial effects, as evidenced by inhibition zones and MIC values. The Higuchi model indicates an excellent fit (R2=0.9988). The MTT assay revealed anti-tumor activity against MCF-7 BC cells, with IC50 of 21.6µg/mL for NG-MOF-5@LNs and demonstrating a total apoptosis effect of 68.2% on MCF-7 cells. Conclusions NG-MOF-5@LNs is anticipated to show as an effective antimicrobial and novel long-term-release antitumor agent and might be more suitable for MCF-7 cell therapy.