Stimuli-responsive chitosan-coated ferrite nanocarriers for targeted capsaicin delivery and core-dependent HepG2-selective bioactivity

Capsaicin is a promising anticancer agent, but its clinical translation is hindered by poor aqueous solubility, low bioavailability, rapid clearance, and dose-limiting irritation, which restrict sustained exposure at tumor sites. Existing formulations only partially overcome these limitations and often lack tumor-microenvironment–responsive release or a clear understanding of how carrier composition modulates biological outcomes. Here, chitosan-coated zinc ferrite (ZFO@CS) and manganese ferrite (MFO@CS) nanocarriers were developed as pH- and glutathione-responsive platforms for capsaicin delivery. The nanocarriers exhibited nanoscale hydrodynamic diameters (~ 120–500 nm) and highly positive zeta potentials (+ 30 to + 50 mV), enabling high encapsulation efficiencies (up to ~ 88%) and colloidal stability. Under physiological pH 7.4, less than 10% of the loaded drug was released over 48 h, whereas ~ 30–40% was liberated under acidic, glutathione-rich conditions mimicking the tumor microenvironment, indicating dual stimulus-triggered behavior. Encapsulation improved capsaicin’s selective cytotoxicity toward HepG2 liver cancer cells, with CAP-MFO@CS achieving a higher therapeutic index than free capsaicin, while maintaining acceptable compatibility with normal WI-38 fibroblasts. The nanocarriers also enhanced antibacterial and antioxidant activities. DNA binding and stopped-flow kinetics revealed that ferrite core composition modulates binding affinity and kinetic stability of DNA–nanocomposite complexes, providing a mechanistic link between material properties and bioactivity. These findings demonstrate that core-dependent design of ferrite–chitosan nanocarriers can improve capsaicin bioavailability, selectivity, and multifunctional therapeutic performance.