Cabazitaxel (CTX) is a potent chemotherapeutic agent, but its clinical application is limited by serious side effects, poor tumor selectivity, and rapid systemic clearance. Inspired by the clinical success of albumin-bound paclitaxel (Abraxane^®) and the high affinity of CTX for human serum albumin (HSA), we aimed to develop a stable and tumor-responsive albumin-based delivery system for CTX using disulfide bond reorganization strategy. Intramolecular disulfide bonds in HSA were briefly broken by various reducing agent to promote CTX loading, followed by the recombination of intermolecular disulfide bonds to form albumin nanoparticles. Compared with nanoparticles prepared using the traditional Nab™ method (Nab@HSA NPs), which was employed in the preparation of Abraxane^®, those prepared via the L-cysteine-based disulfide bond reorganization strategy (L-Cys@HSA NPs) showed improved stability and reduction-responsive drug release. In vivo studies confirmed that L-Cys@HSA NPs significantly enhanced the pharmacokinetic profile and tumor accumulation of CTX. Consequently, L-Cys@HSA NPs demonstrated the strongest antitumor efficacy while maintaining high level of safety. Overall, this disulfide bond reorganization strategy provides a robust platform for the design of albumin-based nanomedicine and enables the efficient delivery of chemotherapeutics.