Bioactive Artificial Cells as Autonomous Metabolic Actuators Enable Bidirectional Communication with Tumor Cells.

Artificial cells (ACs) offer a powerful platform to reprogram metabolic signaling in complex tissue environments by replicating key biological functions without the full complexity of living cells. However, achieving autonomous metabolite exchange and stable integration with living tissues remains a major challenge. Here, we report the development of proteinosome-based ACs equipped with a minimal metabolism to mediate bidirectional communication with glycolytic tumor cells. These tumors accumulate lactate, a metabolic byproduct that promotes immunosuppression and metastasis. Although lactate oxidase (LOx) can degrade lactate, its oxidation product, pyruvate, may inadvertently fuel tumor growth. To overcome this limitation, we engineered dual-processor ACs coencapsulating LOx and pyruvate decarboxylase (PDC), enabling selective conversion of lactate into cytotoxic acetaldehyde while suppressing pyruvate and hydrogen peroxide accumulation. These ACs demonstrate sustained catalytic activity, maintain reactive oxygen species homeostasis, and remain functional when integrated in 3D tumor spheroids. Crucially, they engage in autonomous, bidirectional metabolite exchange, preferentially with cancer cells over normal cells, dynamically rewiring important metabolites of the tumor microenvironment and suppressing cell viability. This work establishes synthetic metabolic biointerfaces as programmable actuators capable of reshaping pathological signaling in cancer tissues.