ABSTRACT Up to 90 million surgical incisions are performed every year within the United States and despite improvements in surgical techniques, administration of antimicrobial prophylaxis, and surveillance protocols, surgical site infections (SSIs) remain a major clinical challenge. SSIs occur in 2-5% of patients undergoing surgery in the United States alone, impact 300,000-500,000 lives each year, and are associated with a 2-11 times greater risk of death compared to patients without SSIs. SSIs pose particularly serious challenges to patients with diabetes and to those with compromised immune systems. The most common cause of SSI is Staphylococcus aureus which occurs in 20% of SSIs among hospitals that report to the CDC and 37% among the community hospitals; methicillin-resistant S. aureus (MRSA) is the most common pathogen in community hospitals. Current clinical practices to treat incisions and traumatic lacerations include sutures, adhesives, tape, or staples with or without antimicrobial incorporation. However, these technologies are susceptible to infection, wound dehiscence, and poor or delayed biomechanical recoveries. Thus, there exists an urgent need to prevent and combat SSIs efficiently in order to decrease patient mortality, time, and costs associated with recovery. Here, we propose the development of novel laser-activated nanoglues (LANGs) for simultaneously sealing incisions together with the ability to combat short-term and longer term or repeat SSIs. Laser sealing of incisions using LANGs will result in a leak-proof seal throughout the incision, thereby preventing the infiltration of microorganisms into the wound. Silver nanoprisms (AgNPs) in the LANGs absorb near infrared (NIR) light for rapid tissue sealing and can also serve as sources of silver for antibacterial activity. Previous work in our laboratory has indicated that gold nanorod-silk LANGs can be effectively used to seal incisions in mice and resist bacterial infiltration. The efficacy for skin sealing and MRSA infection control of LANG formulations will be evaluated in immunocompetent, immunodeficient, as well as diabetic and obese mice. LANGs will also be investigated as depots for longer-term delivery of encapsulated antibiotics like vancomycin, which will serve to better resist longer-term and repeat infections in susceptible hosts. Taken together, LANGs have tremendous translational potential as a multi- faceted approach for effective tissue sealing and SSI control in surgery, and will see particular applicability in immunodeficient and diabetic patients.