Abstract This proposal describes the synthesis, characterization, and thorough evaluation of the first supramolecular hybrid hydrogel burn dressing. Our design goals are a) on-demand dissolubility -for easy trauma-free removal from burn wound-, b) integrated antimicrobial activity - for infection management-, and c) self-healing – for problem-free application and use. Burn injuries are one of the most prevalent, devastating, and demanding critical care problems, worldwide. Nearly every minute, someone in the US sustains a serious burn injury, and each day over 300 children visit emergency rooms and 2 of them die due to burn injuries. Millions, globally, suffer from burn-related disabilities with heavy psychological, emotional, and economic consequences on the survivors and their families. Burn dressing removal is reportedly the time of most pain (after the burn itself), and opioids are the primary treatment for such pain. The burn dressing change for a typical injury with intensive care unit level care is at least 57.6 minutes. The time and complexity of the process further grow with the frequently applied anesthesia. Importantly, repeated painful dressing changes and wound infection cause a higher predisposition to life- threatening sepsis and multi-organ failure. Currently available burn dressings – used clinically – adhere to the wound surface and are surgically or mechanically debrided from the wound. This results in the traumatization of newly epithelialized tissues, delayed healing and severe pain. We, thus, propose to create a supramolecular hybrid hydrogel combining the host-guest chemistry (cucurbituril [7]-hosted cationic copolymer) with inorganic components (i.e., clay) (Aim1). The unique feature of this hydrogel will be its high biocompatibility and ability to be dissolved on-demand via adamantane/diamantane derivatives, easily and quickly removed and eliminate debridement. This will reduce extreme pain and suffering (by drastically reducing time of pain). The proposed hydrogel will also be embedded with antibiotics to reduce bacterial infection. We will test this hydrogel through both in vitro (mouse and human cells, Aim 2) and in vivo (mouse, Aim 3) and preclinical (swine, Aim 3) experiments. Overall, our goal is to promote better burn wound healing, deter infection and provide pain-free burn care for patients, in line with the mission of NIAMS. This project falls under the umbrella of regenerative medicine (wound healing, tissue repair, regeneration) and treatment of large-area acute skin wounds (burns and trauma) highlighted in the NIAMS Strategic Plan for FY 2020-2024. The project also focuses on a) improving the patient experience (reducing pain), and b) treating co-occuring conditions of burn wounds and infections, two focus areas of NIAMS.