<p>The therapeutic use of copper oxide nanoparticles for wound healing is limited by intrinsic cytotoxicity arising from uncontrolled Cu²⁺ release. This study reports a hierarchical nanocomposite design that decouples bioactivity from cytotoxicity via green sol–gel synthesis followed by polymer-mediated nanoconfinement. Green synthesis using <i>Rhus coriaria</i> (sumac) extract contributed to structural changes through two primary mechanisms: (i) phytochemicals adsorbed to growing crystal surfaces, limiting Ostwald ripening and restricting crystallite growth; (ii) incorporation of organic capping agents induced lattice distortions during nucleation. Williamson-Hall analysis revealed a 54% reduction in crystallite size (to 13.7 nm) and an 89% increase in lattice microstrain (ε = 4.81 × 10^-3) compared to conventionally synthesized CuO NPs. These green-synthesized CuO NPs were encapsulated within a chitosan matrix via coordination chemistry. X-ray diffraction showed severe attenuation of CuO Bragg peaks, confirming nanoconfinement of crystalline domains below 5 nm. Fourier-transform infrared spectroscopy revealed a hypsochromic shift of the amide I band from 1653 cm^–1 to 1567 cm^–1, evidencing interfacial Cu²⁺–NH₂coordination. At 125 µg/mL, the nanocomposite maintained 94.0% viability in human dermal fibroblasts versus 4.9% for bare CuO NPs, while enhancing fibroblast migration by 44% and achieving 85.4% in vitro wound closure over 48 h. The nanocomposite also exhibited broad-spectrum antibacterial activity (inhibition zones up to 20 mm), comparable to gentamicin. This work demonstrates that green sol–gel synthesis combined with polymer nanoconfinement produces a hierarchical chitosan-CuO hybrid that balances safety and efficacy, offering a generalizable design strategy for metal-oxide nanotherapeutics.</p> Graphical Abstract <p></p>