Engineered zwitterion-nanodelivery for precision targeting of brain metastases.

The central nervous system is a critical reservoir for cancer metastasis, underscoring the urgent need for effective strategies for targeted drug delivery that minimize systemic side effects. Here, we present a zwitterionic polycarboxybetaine (PCB) designed to achieve selective accumulation within the tumor vasculature of brain metastases, thereby facilitating the rapid release of therapeutics without relying on external stimuli in preclinical models. PCB selectively targets the betaine-γ-aminobutyric acid transporter 1 (BGT1) at the blood-brain-tumor barrier (BBTB), enabling localized enrichment of nanoparticles within the tumor vasculature. The intrinsic mechanical flexibility of PCB activates the Piezo1 ion channel in endothelial cells, resulting in calcium ion influx and enhanced calpain activity, which together facilitate the degradation of VE-cadherin. The burst-release mechanism improves vascular permeability and compromises the integrity of the tumor vascular barrier, allowing for the swift release of encapsulated therapeutics and promoting extensive drug distribution within the tumor microenvironment. Notably, PCB encapsulating either osimertinib or cisplatin demonstrates therapeutic efficacy, intratumoral targeting, and favorable biological safety in disease models. These findings indicate that this zwitterion-functionalized platform effectively surmounts the challenges posed by the BBTB, supporting improved drug delivery and therapeutic efficacy in brain metastases.