Restoration of m6A-Modified circPSMB1 Suppresses Chordoma Progression and Enables Local Nanotherapeutic Intervention.

Chordoma is a rare malignant bone tumor characterized by aggressive local invasion and high recurrence, yet its molecular regulatory mechanisms remain poorly understood. Circular RNAs (circRNAs) have emerged as important regulators of gene expression, but how circRNA epigenetic modifications contribute to oncogenic signaling is largely unknown. Here, we identify circPSMB1 as a significantly downregulated circRNA in chordoma tissues through high-throughput circRNA sequencing. Functionally, circPSMB1 suppresses chordoma cell proliferation, migration, and invasion in vitro and inhibits tumor growth in vivo. Mechanistically, METTL3-dependent m6A modification facilitates the association of circPSMB1 with the m6A reader HNRNPA2B1. CircPSMB1 competitively reduces the association of HNRNPA2B1 with c-MYC mRNA, thereby decreasing c-MYC protein expression without altering c-MYC transcript abundance. Beyond mechanistic insight, we develop an injectable circPSMB1-loaded HMnO2-based nanohydrogel that enables sustained circRNA delivery and tumor microenvironment-responsive therapy, effectively suppressing chordoma progression in vivo.