Homeostatic artificial cells enable self-protection in prototissue spheroids

The bigger pictureLiving cells form tissues with specialized functions that maintain homeostasis through feedback-regulated operations. In tissues, cellular communication and collective behavior are crucial for coordinating tasks and ensuring overall functionality. Developing artificial cells (ACs) that can be organized into prototissues to mimic these behaviors is a significant advancement toward creating functional AC systems. These systems are essential for understanding how to design communication networks and collective behaviors, deciphering life's fundamental principles, and advancing biomedical applications. Here, we create AC-based prototissue spheroids that stabilize their microenvironment against external pH threats using a homeostasis mechanism encoded within individual ACs. Like living tissues, these prototissues communicate chemically to collectively resist environmental challenges, paving the way for more advanced artificial tissues in the future.Highlights•Microfluidic production of artificial cells (ACs) with reversible permeability•Homeostatic ACs modulate external and internal pH via chemo-structural feedback•Prototissues collectively stabilize internal states against external threats•Inter-AC communication in mixed prototissues counteracts internal threatsSummaryPrototissues made from artificial cells (ACs) aim to replicate the behaviors of living tissues, such as communication, collective behavior, and homeostasis. Despite progress in developing diverse AC types, building prototissues and achieving effective communication as well as collective behavior in such prototissues remain challenging. We introduce ACs with an intrinsic homeostatic pH control mechanism that can be organized into prototissues to collectively maintain a stable microenvironment and protect cargo from environmental pH fluctuations. These ACs contain pH-modulating enzymes within a pH-sensitive membrane, allowing for self-regulation through chemo-structural feedback. They adjust pH by importing substrates within a specific pH range and self-regulate to control substrate influx. This enables them to modulate local pH, manage cargo release, and facilitate interactive communication in organized spheroids. Our findings demonstrate the potential of homeostatic ACs to create advanced synthetic tissue mimics, replicating protective and communicative functions of living tissues for biomedical and tissue engineering applications.Graphical abstract