Microglia at the core of brain inflammaging: advanced in vitro and neuroimmune organoid platforms for neurotheranostics

Komleva Yulia K.,  Satish Anakha, Berdnikov Arseniy K., Rozanova Natalia A., Kolotyeva Natalia A., Tregub Pavel P., Saridis Mikis, Yurchenko Stanislav O., and  Salmina Alla B.
Springer Nature 2026 https://doi.org/10.1140/epjs/s11734-026-02209-x
Microglia are the principal innate immune cells of the central nervous system and play a central role in regulating neuroinflammation across the lifespan. Aging profoundly reshapes microglial phenotype and function, promoting a chronic, low-grade inflammatory state referred to as inflammaging, which contributes to cognitive decline and neurodegenerative disease. Experimental modeling of these age-associated microglial states remains challenging due to the unique ontogeny, plasticity, and context-dependent behavior of microglia. In this review, we critically evaluate the current spectrum of in vitro and ex vivo models used to study microglia, ranging from classical primary cultures and immortalized cell lines to advanced human-relevant platforms, including induced pluripotent stem cell-derived microglia, organotypic brain slices, neuroimmune organoids, and microphysiological systems. Particular emphasis is placed on the capacity of these technologies to support neurotheranostic development by enabling mechanistic dissection of microglial aging, immunosenescence, and inflammasome-driven neuroinflammation, with a focus on NLRP3 signaling. We further discuss emerging integrative strategies that combine advanced neuroimmune platforms with artificial intelligence, machine learning, and digital twin frameworks to enhance data integration, predictive modeling, and translational relevance. Together, these approaches position neuroimmune organoids and microphysiological systems as enabling technologies for next-generation neurotheranostics targeting age-associated neuroinflammatory processes.