Phenylboronic Acid-Functionalized, Naringin-Loaded Zinc Oxide Nanocarriers: A pH-Responsive, Actively-Targeted Nanocarrier for Breast Cancer Therapy

Conventional breast cancer chemotherapy is limited by poor tumour selectivity and systemic toxicity, motivating stimuli-responsive, actively-targeted nanocarriers. Here, naringin (NG)-loaded zinc oxide nanoparticles (NG-ZnONPs) were synthesised via alkaline co-precipitation using a Quality-by-Design approach with a Box-Behnken Design, then surface-functionalised by silanization and 4-formylphenylboronic acid conjugation to form a pH-labile Schiff-base linkage (PBA-NG-ZnONPs) for sialic-acid-receptor-mediated active targeting. Surface plasmon resonance (UV-Vis, 356 nm) and the imine bond (FTIR, 1560 cm⁻¹) confirmed successful conjugation. XRD/SAED confirmed a hexagonal wurtzite structure (20.1–20.3 nm), while TEM revealed anisotropic, organically-capped nanorods (73.0–120 × 19.5–30.8 nm). PBA-NG-ZnONPs showed a hydrodynamic diameter of 341.9 nm (PDI 0.386, ZP −9.4 mV), with 91.14% entrapment efficiency for NG-ZnONPs and 89.69% DEE and 36.51% DLC for PBA-NG-ZnONPs. Dialysis studies confirmed pH-dependent, acid-triggered release (41.40% at pH 5.0, 21.76% at pH 6.0, 3.07% at pH 7.4; 48 h). NG-ZnONPs showed potent antioxidant activity (DPPH IC₅₀ = 236.88 µg/mL; ABTS IC₅₀ = 229.06 µg/mL), while PBA-NG-ZnONPs showed nearly 3-fold greater cytotoxicity against MCF-7 cells (IC₅₀ = 56.51 µg/mL) than free naringin, unmodified ZnONPs, or non-functionalized NG-ZnONPs. These results suggest that PBA-NG-ZnONPs are an efficient, stimuli-sensitive drug-delivery platform with promise for site-specific cancer treatment, combining two distinct approaches: sialic acid receptor-mediated cellular targeting and endosomal pH-triggered drug release.