Influence of end-group functionality and composition on the antifungal activity and biocompatibility of polyacrylamide-based polymers

• Optimal Chain Length: The study identified that polymers with a specific, shorter chain length (with a degree of polymerization,) are the most potent and selective against Candida species. • End-Group Influence: The chemistry of the polymer’s end-groups was found to be a critical factor in determining its therapeutic performance, significantly impacting both antifungal activity and toxicity to host cells. • Interdependence of Design Elements: The research highlights a crucial relationship between the hydrophobicity of the polymer’s main chain and the hydrophobicity of its end-groups. Optimizing both is necessary for maximum selectivity. • Enhanced Biocompatibility: By modifying the end-groups, the authors were able to reduce cytotoxicity, thereby improving the safety profile of the antifungal polymers. • Integrated Design Strategy: The paper establishes a new, rational design approach that integrates molecular weight, polymer composition, and end-group engineering to create highly effective and selective antifungal agents. Drug-resistant invasive fungal infections are a growing health threat, prompting the development of synthetic antifungal polymers as alternative therapeutic platforms. Here, we report the systematic design of polyacrylamide terpolymers synthesized via photoinduced electron/energy transfer–RAFT (PET-RAFT) polymerization. Molecular weight, varied by controlling chain length, determined antifungal selectivity: shorter polymers exhibited superior selectivity against Candida species. Chain-length thresholds were identified for Candida albicans and Candida tropicalis , while Candida parapsilosis responded most strongly to the lowest-molecular-weight (MW) analogues. To investigate the combined influence of the polymer end-group functionality and molecular composition, three distinct chain-transfer agents (RAFT agents) were employed, and composition was systematically tuned. Selective ω– end-group modification was then performed to introduce either hydroxyl (–OH) or hydrophobic heptyl groups. End-group functionality, together with composition control, governed structure–activity relationships, enabling the precise tuning of antifungal activity and biocompatibility. This integrated design strategy establishes molecular-level principles to guide the rational development of antifungal polymers.