Padlock-designed MOFs triggers an "avalanche effect" to enhance apoptosis and suppress metastasis in central nervous system lymphoma.

The increasing incidence of central nervous system lymphoma (CNSL) is hindered by the blood-brain barrier and costly prolonged drug development. To overcome these obstacles, we developed a carboplatin lock-designed MOF (Pt-MOFs@Glu) targeting intestinal macrophages for brain-directed drug transport. Single-cell RNA sequencing analyses revealed that intestinal macrophages migrate to the brain in response to chemokines. Building on this insight, Pt-MOFs@Glu was designed to engage these cells for precise delivery. Comprising carboplatin, pyrazine-quinoxaline, and β-glucan, the system induces an "avalanche effect" in the CNSL microenvironment, promoting tumor apoptosis and inhibiting metastasis. Combining pyrazine-quinoxaline to lock carboplatin and β-glucan to boost targeting, immunity, and oral absorption, the system enables ROS-triggered drug release, efficiently crosses the gastrointestinal tract and BBB, and synergizes chemo-immunotherapy to enhance therapeutic efficacy. This approach redefines CNSL treatment by harnessing the gut-brain axis, offering a transformative pathway to overcoming therapeutic barriers and improving patient outcomes.