Nanotandem-rocket releases messenger to disrupt metabolic communication for antitumor immunotherapy

Metabolic communication between intracellular metabolism and extracellular microenvironment is responsible for celluar metabolism balance and cell survival. Tumor cells adaptively regulate metabolic communication to promote hyperproliferation and immunosuppression. Herein, nanotandem-rockets (hyaluronic acid modified Mg₅(CO₃)₄(OH)₂ (H-MCH)) are developed for stepwisely disrupting metabolic communication to activate antitumor immunity. Benefiting from the nanotandem-rocket structure, H-MCH nanoplates successively disrupt the extracellular metabolite transport and intracellular carbohydrate metabolism. Theoretical simulation together with metabolomic analysis discloses the underlying mechanism of H-MCH nanotandem-rockets. The extra-/intra-celluar interruption of metabolic communication provides H-MCH nanotandem-rockets with high efficiency in tumor eradication. Moreover, the interference of metabolic communication reverses immunosuppression to facilitate the intratumoral infiltration of immune cells. With H-MCH nanotandem-rockets as an in situ vaccine, systemic antitumor immunity and immune memory effect are fabricated to eliminate tumor metastasis and recurrence. Different from traditional metabolic poisons (e.g., arsenic or cyanide), the structure of nanotandem-rockets endows chemical messengers with selective regulation to tumor metabolic communication, but with minimal influence to normal tissues. The nanotandem-rockets provide a powerful paltform to augment the regulating actitiy of chemical messengers in metabolic communication. We expect our discovery of disrupting tumor metabolic communication with chemical messengers will be a powerful strategy for tumor therapy with vast practical applications.