<p>Nanodrug delivery systems for ferroptosis tumor therapy have been extensively developed. However, some key parameters, such as obstinate intracellular redox balance of tumor microenvironment (TME) and low tumor targeting or penetration, immensely reduce the efficacy of ferroptosis. Therefore, novel GFGH nanoparticles (NPs) were successfully constructed based on metal coordination self-assembly including Gambogic acid (GA), Fe³⁺, glucose oxidase (GOX) and hyaluronic acid (HA). Due to its shuttle-like shape and HA loading, GFGH NPs enhanced tumor penetration with shuttle-like shape and enhancing cellular uptake by CD44. At GSH-overexpressed tumor cells, the disassembly of GFGH NPs was accompanied by the depletion of GSH and release of Fe²⁺, GOX and GA. GOX consumed intracellular glucose to enhance intratumoral H₂O₂ for stimulating abundant hydroxyl radicals via the Fenton reaction of Fe²⁺. GA further depleted residual intracellular GSH and downregulated GPX4, achieving a multi-pathway to break intracellular redox balance for boosting specific ferroptosis therapy. In vivo and in vitro results indicated that GFGH NPs exhibited outstanding antitumor efficacy on both normal tumor models and large tumor models. In summary, shuttle-like-shaped GFGH NPs with tumor targeting and deep tumor penetrating provided a promotion strategy for cascade-amplified tumor-specific ferroptosis therapy.</p>