doi:10.1021/acsami.5c08968engMattar, ImanLanda, GuillermoFrutos-Lizano, MarinaIzquierdo, NataliaTapia, ElenaPerez, MartaLujan, LluisIrusta, SilviaMendoza, GraciaArruebo, ManuelMultifunctional 3D-Printed Wound Dressings Containing a Combination of Synergistic Antimicrobials in the Management of MRSA Infected Topical WoundsART-2025-145322Despite increased pre- and postoperative care and aseptic practices in surgical rooms, methicillin-resistant Staphylococcus aureus (MRSA) continues to colonize acute surgical wounds. MRSA is also present in chronic nonhealing wounds, such as diabetic foot and pressure ulcers. In this work, advanced antimicrobial-loaded wound dressings are 3D printed using fused deposition modeling. To achieve a high antimicrobial effect, the topical antiseptic octenidine (OCT) was incorporated into the pellets used in the feeder of the extruder prior to fused modeling. Lysostaphin (LYS), a lytic enzyme that cleaves MRSA peptidoglycan, was incorporated by supramolecular interactions on the surface of the OCT-loaded dressings to exploit the anti-MRSA synergy identified here between OCT and LYS showing a fractional inhibition concentration index (FICI) of 0.156. Minimum inhibitory concentration (MIC) and bactericidal concentration (MBC) values for the OCT were 1 and 25 μg/mL, respectively, whereas the MIC and MBC values for the LYS were 0.1 and 0.2 μg/mL, respectively. The resulting dressings completely eradicate MRSA USA 300 inocula (105 CFU/mL) in 96 h. The bactericidal mechanisms exerted by these dressings were identified through molecular techniques, showing lytic effects on the cell wall peptidoglycans of treated bacteria. Additionally, OCT at 1 μg/mL was able to reduce lipopolysaccharide (100 ng/mL)-induced NO production on murine J774A.1 macrophages by more than 90% demonstrating its simultaneous anti-inflammatory action. This effect was also corroborated by the qRT-PCR analysis of several pro-inflammatory genes including IL-1β, IL-6, TNF-α, and Nos2. The combination of OCT and LYS within the dressings reveals higher in vivo therapeutic effects compared to free compounds or individual antimicrobial-loaded dressings. In vitro and in preclinical models, the use of OCT-LYS dressings effectively reduces MRSA bioburden and inflammation, promoting fast wound healing.2025http://zaguan.unizar.es/record/16275210.1021/acsami.5c08968http://zaguan.unizar.es/record/162752oai:zaguan.unizar.es:162752info:eu-repo/grantAgreement/ES/AEI/CEX2023-001286-Sinfo:eu-repo/grantAgreement/ES/ISCIII/FORT23-00028info:eu-repo/grantAgreement/ES/ISCIII/MS19-00092info:eu-repo/grantAgreement/ES/MICINN/PID2020-113987RB-I00info:eu-repo/grantAgreement/ES/MICINN/PID2023-146091OB-I00info:eu-repo/grantAgreement/ES/MICINN PRE2022-105709info:eu-repo/grantAgreement/ES/UZ/LMA-ELECMI ICTSACS applied materials & interfaces 17, 34 (2025), 47951-47968byhttps://creativecommons.org/licenses/by/4.0/deed.esinfo:eu-repo/semantics/openAccess