Lipidomic signatures of CNS ischemic injury and their modulation by immunomodulatory hydrogels

Ischemic injury in the central nervous system (CNS) triggers profound metabolic remodeling that influences inflammation, repair, and cellular survival. Among these changes, lipids play key structural and signaling roles, yet the spatial distribution of lipid species after CNS ischemia, and how they respond to local immunomodulation, remains poorly understood. Here, we used infrared matrix-assisted laser desorption electrospray ionization mass spectrometry imaging (IR-MALDESI MSI) and immunofluorescence microscopy to map lipid and metabolite distributions in a mouse photothrombotic model of CNS ischemia. We first defined lipidomic shifts induced by ischemic injury alone, which included accumulation of sphingolipids and fatty acids (e.g., ceramides, sphingomyelins, and polyunsaturated fatty acids) with concurrent depletion of glycerophospholipids (e.g., phosphatidylethanolamines, phosphatidylcholines). We then examined how hyaluronic acid-based microporous annealed particle (MAP) hydrogels modulate these injury-associated lipid signatures. Injection of an immunomodulatory polysialic acid MAP (PSA-MAP) hydrogel altered cholesterol metabolism within the peri-infarct region of the lesion, increasing the ratio of cholesteryl ester to cholesterol-a lipid signature that inversely corresponds to cardiovascular disease states. Together, these data reveal that CNS ischemic injury drives characteristic lipid remodeling, and that biomaterial immunomodulation can reprogram this metabolic landscape toward a reparative state.