Abstract

Malignant melanoma is an aggressive skin malignancy that is frequently complicated by bacterial infections during postoperative recovery. However, current therapeutic strategies rarely address infection-associated complications, highlighting the need for multifunctional biomaterials capable of simultaneously targeting tumor cells and pathogenic bacteria. Herein, retinoic acid (RA)-functionalized chitosan polycationic conjugates were well engineered to achieve integrated anticancer and antimicrobial activity. The incorporation of quaternary ammonium groups together with hydrophobic RA moieties enabled the rational regulation of charge density and hydrophilic–hydrophobic balance, resulting in improved aqueous solubility, bioactivity, and biocompatibility. The optimized conjugate inhibited melanoma cell proliferation (IC50 = 4 μg/mL) and exhibited broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria, with MIC values of 4–32 μg/mL. Mechanistic studies suggested that the polycationic conjugates act through multiple coordinated mechanisms, including membrane disruption, RAR/RXR-related signaling, ROS generation, and necrosis/apoptosis induction. In vivo experiments further demonstrated significant antitumor suppression (∼70% reduction in tumor volume) together with effective inhibition of S. aureus infection at wound sites (∼1.5-log reduction). These findings highlight RA-functionalized chitosan polycations as a promising multifunctional biomaterial system for melanoma therapy while addressing infection-associated complications.