Gut-derived macrophages as endogenous carriers for brain-targeted cisplatin nanotherapy.

Central nervous system lymphoma (CNSL) is difficult to treat owing to the blood-brain barrier and limited efficacy of conventional chemotherapy. Herein, we report a bioinspired cisplatin-based nanomedicine that exploits gut-derived macrophages as endogenous carriers for brain-targeted delivery. Single-cell transcriptomic analyses of human and murine CNSL samples revealed a previously unrecognized enrichment of intestinal macrophages within tumor lesions, suggesting a gut-immune-brain trafficking route. Guided by this insight, a hierarchical nanostructure (Cdp NM) wasconstructed, consisting of a cisplatin-pyrazinoquinoxaline core enabling controlled drug release and a trehalose shell that promotes macrophage uptake via organic anion transport pathways while inducing autophagy. Following oral administration, Cdp NMs are internalized by intestinal macrophages and transported to brain tumors. Under laser irradiation, a slow-light effect triggers localized cisplatin release, resulting in efficient tumor cell ablation. Concurrently, autophagy activation in macrophages enhances antitumor immune responses. In both primary and secondary CNSL models, this system achieved significant tumor suppression and prolonged survival. This work establishes a chemically programmable strategy that leverages endogenous immune cells for noninvasive brain-targeted chemotherapy, offering a new paradigm for treating intracranial malignancies.