02002nas a2200277   4500000000100000000000100001008004100002260001500043653001800058653002000076653002400096653002500120653002300145100001800168700001500186700002000201700001600221700002200237700002900259700001600288700001700304245014500321856005500466520118900521022001401710       2026                            d  c2026-07-1510aAssay systems10aNeuroimmunology10aNeurological models10aPhenotypic screening10aTissue engineering1 aJiajing Zhang1 aYi Wei Lim1 aAngelica Medina1 aYu-Chi Chen1 aYining Irene Wang1 aMartin Carrasco Carvajal1 aMarc Ferrer1 aEmily M. Lee00aMicroglia integrated neural spheroids enable neuroinflammatory responses and correct network dysfunction induced by alpha-synuclein mutation  uhttps://www.nature.com/articles/s42003-026-10696-w3 aMicroglia are the primary resident immune cells of the brain, playing both protective and deleterious roles in neurological diseases, which makes them an enticing therapeutic target. Here we developed a Neural Microglia Integrated Multicellular iPSC-derived Cultured Spheroids (NeuroMIMICS) system that enables measurements of both neural network activity and immune responses using human iPSC-derived microglia, astrocytes, and neurons. We validated microglia functionalities in these neural tri-cultures including phagocytic activity, directed motility, and inflammatory responses. RNAseq analysis revealed a phenotypical acquisition of immune functionality via microglia incorporation, supported by increased cytokine production in spheroids challenged with pathogen-like insults. We then demonstrated that the incorporation of healthy microglia corrected alpha-synuclein A53T-mediated dysfunctional phenotypes in the neural spheroids. This work demonstrates a unique immunocompetent functional neural model that is robust and suited for high-throughput screening, laying the groundwork for its application to accelerate the discovery of new therapeutics for neurological diseases.  a2399-3642