Background <p>Postoperative chemotherapy is essential for glioma treatment but faces two major limitations: the blood-brain barrier (BBB) restricts drug delivery, and tumor chemoresistance reduces therapeutic efficacy. To circumvent these hurdles, we engineered a 3D-bioprinted, sustained-release microneedle patches (MNs@GFD) that can be affixed directly to the postoperative tumor cavity, thereby bypassing the BBB and providing localized, long-term drug delivery. The patch incorporates gambogic acid-iron-doxorubicin nanozymes (GAFe@DOX, GFD) that simultaneously remodel the hypoxic tumor microenvironment via multi-enzyme activity and prime tumor cells for doxorubicin (DOX) cytotoxicity through ferroptosis.</p> Results <p>Comprehensive characterization confirmed successful construction of MNs@GFD and demonstrated potent catalase-, peroxidase- and oxidase-like activities that alleviated intratumoral hypoxia. Multi-omics profiling revealed that GFD orchestrates a transcriptional program that robustly up-regulated pro-ferroptosis genes (ACSL4, COX2) while suppressing anti-ferroptosis guardians (GPX4, FTH1), leading to iron-dependent lipid peroxidation, mitochondrial collapse and concomitant apoptosis. Correspondingly, in vitro assays showed rapid and extensive death of glioma cells exposed to GFD, and in vivo studies in a post-surgical orthotopic model demonstrated that MNs@GFD markedly hindered tumor regrowth without systemic toxicity.</p> Conclusion <p>MNs@GFD integrates localized drug release, BBB bypass, hypoxia relief and ferroptosis-mediated chemosensitization into a single platform, establishing a powerful and clinically translatable postoperative chemotherapeutic strategy against glioma.</p> <?tk 4?> Graphical Abstract<?tk 4?> <p><?tk 4?><?tk 4?></p>