Chitosan polymeric nanoparticles loaded with a grapefruit-derived flavonoid-rich extract containing naringenin: antibacterial activity, cytotoxicity evaluation and DFT interaction analysis

Naringenin is a bioactive flavonoid with reported anti-bacterial and cytotoxic properties; however, its biomedical applicability is limited by poor aqueous solubility and restricted bioavailability. In this study, chitosan-based polymeric nanoparticles loaded with naringenin (Chito-NPs/NAR-EtOH) were designed as a biocompatible delivery platform to enhance NAR-ETOH dispersion and biological performance. The nanoformulation exhibited a high encapsulation efficiency (84.2%). Biological evaluation revealed that Chito-NPs/NAR-EtOH modestly improved antibacterial activity compared to free ethanolic naringenin extract (NAR-EtOH), particularly against Salmonella spp . and Klebsiella pneumoniae , as evidenced by enlarged inhibition zones and reduced MIC values. In contrast, cytotoxicity assessment against MCF-7, A549, and DLD-1 cancer cell lines demonstrated only moderate cytotoxic activity (IC₅₀ ≈ 122–128 µM) with limited selectivity, as nano-encapsulation increased toxicity toward normal human dermal fibroblasts. While nano-encapsulation modestly improved antibacterial activity, it did not enhance cancer-selective cytotoxicity and increased toxicity toward normal cells, limiting the therapeutic advantage of the current formulation. DFT calculations provided qualitative insight into the possible intermolecular interactions between NAR-EtOH and chitosan, supporting the experimental observations of nanoformulation assembly. Overall, while chitosan nano-encapsulation modestly improves the anti-bacterial performance of NAR-EtOH through enhanced dispersion and formulation performance, it does not confer a therapeutic advantage in terms of selective cytotoxicity toward cancer cells in the present formulation. These findings highlight the importance of formulation-dependent biological outcomes and emphasize chitosan’s role as an effective carrier rather than an intrinsic enhancer of cancer cell cytotoxic potency.