IntroductionIntracranial tumor represents a common type of tumor that poses a great threat to human health, whether it is primary or metastatic1,2,3. However, although surgery combined with chemotherapy is a clinically standardized treatment strategy, the overall survival time is only approximately 15–17 months4,5. There are two main reasons for the above results6,7,8: On the one hand, the presence of BBB severely restricts the retention of drugs in intracranial tumor lesions9,10; On the other hand, it has been reported that the high expression of PD-L1 of intracranial tumor cells after chemotherapy intensifies the inhibition of tumor immune microenvironment, seriously hindering the efficacy of immunotherapy11,12,13.Serum albumin (SA), the largest proportion protein in plasma, has been widely applied in the biomedical field due to its low immunogenicity, long circulation time and tumor-homing capability14,15,16,17,18,19. Among albumin-based platforms, Abraxane (nab-paclitaxel), approved by the FDA in 2005, represents a landmark in clinical translation20,21. Nevertheless, its clinical utility remains constrained by limitations in both formulation complexity and pharmacokinetics22,23,24. The clinical advantage of Abraxane over Taxol primarily stems from excipient substitution rather than substantial improvements in drug release kinetics. Due to insufficient drug-albumin affinity, paclitaxel is rapidly dissociated and cleared post-administration, resulting in systemic exposure and reduced therapeutic efficiency25. Furthermore, as Abraxane lacks the ability to cross the BBB, it is unable to enter the brain to kill tumor cells, which has led to slow progress in Abraxane against intracranial tumors. Hence, minimizing premature drug release in circulation and endowing ability to cross BBB are critical for advancing next-generation albumin-based paclitaxel delivery systems for intracranial tumors treatment.Herein, we introduced a TA-Fe3+ biomineralization into the paclitaxel albumin-based paclitaxel nanoparticles (Fe3+@SA-PTX), effectively addressing challenges encountered by albumin-based nanomedicines in intracranial tumors treatment: Firstly, the incorporation of TA-Fe3+ facilitated nanoparticle formation, enabling simple one-step precipitation method to produce nanoparticles with higher drug loading than Abraxane (improved by 9% than Abraxane). Secondly, the albumin layer tightly chelated with Fe3+ and TA, significantly reducing PTX leakage and enhancing nanoparticle stability and pharmacokinetics. Additionally, the surface Fe3+ binds to unsaturated transferrin in the bloodstream, thereby promoting BBB penetration and tumor targeting. Finally, intracellular reduction of Fe3+ to Fe2+ in tumor cells induces ferroptosis, which synergizes with PTX to enhance intracranial tumor suppression. Furthermore, co-administration of Fe3+@SA-PTX and an anti-PD-L1 antibody markedly prolonged survival in tumor-bearing mice.Result and discussionPreparation and characterizations of Fe3+@SA-PTXWe initially screened the formulation ratios for the preparation of Fe3+@SA-PTX nanoparticles. The results (Table S1-S2) demonstrated that Fe3+@SA-PTX nanoparticles prepared at SA: PTX ratios of 10:1 and 8:1 (w: w) exhibited the ideal particle sizes and uniform size distributions, while maintaining excellent stability over 12 h. The Fe3+@SA-PTX nanoparticles prepared at the 6:1 (SA: PTX) ratio exhibited certain alterations in both particle size and size distribution characteristics over 12 h, while there are abrupt alterations in 4:1 and 2:1 group. Next, we further evaluated the encapsulation efficiency and drug loading capacity across the three formulation groups (10:1, 8:1, and 6:1 SA: PTX ratios). Comprehensive analysis demonstrated that while the 6:1 group achieved the highest drug loading (12.3%), this formulation was ultimately excluded due to poor nanoparticle stability. Consequently, the 8:1 ratio was selected as the optimal formulation, exhibiting a drug loading of 10.9%, superior to Abraxane (10%) (Fig. 1c and d). Subsequently, we prepared both SA-PTX and Fe3+@SA-PTX nanoparticles using this optimized ratio (8:1, SA: PTX). The resulting particle size, size distribution and transmission electron microscope image are presented in Fig. 1a. The zeta potential results demonstrated that Fe3+@SA-PTX exhibited reduced electronegativity compared to SA-PTX, providing preliminary evidence for successful TA-Fe3+ coating on the SA-PTX nanoparticles (Fig. 1b). Next, we evaluated the PTX leakage profiles of both SA-PTX and Fe3+@SA-PTX nanoparticles under static conditions during 24 h. The results demonstrated that Fe3+@SA-PTX exhibited significantly slower drug release, indicating that the incorporation of TA-Fe3+ complexes enhanced intermolecular binding forces within the nanoparticle system (Fig. 1e). We subsequently monitored the particle size and size distribution of Fe3+@SA-PTX nanoparticles over a 18-day period. The results demonstrated excellent long-term stability, with no significant alterations in either hydrodynamic diameter or polydispersity (Fig. 1f). Next, we successfully prepared Fe3+@SA-PTX nanoparticles using Cy5-labeled SA and FITC-labeled TA. Fluorescence analysis confirmed the co-localization of both Cy5 and FITC signals, providing evidence for the successful fabrication of the Fe3+@SA-PTX nanocomplex. By adding interfering reagents of different types of intermolecular forces, we investigated the types of key forces maintaining Fe3+@SA-PTX nanoparticles. The results showed that after adding EDTA, the particle size of Fe3+@SA-PTX nanoparticles changed significantly. It is proved that the key force for maintaining Fe3+@SA-PTX nanoparticles is mainly provided by the coordination force.Fig. 1Full size imagePreparation and characterizations of Fe3+@SA-PTX. (a) Particle size results and Transmission electron microscope (TEM) photos. Scale bar = 100 nm. (b) The zeta potential results. (c) The encapsulation rate of Fe3+@SA-PTX in different prescription. (d) The drug loading capacity of Fe3+@SA-PTX in different prescription. (e) The leakage rate of SA-PTX and Fe3+@SA-PTX during 24 h. (f) The change of size and PDI of Fe3+@SA-PTX during 18 days. (g) Fluorescence colocalization experiment of SA and TA-Fe3+, Scale bar = 1 μm. (h) The change of size of Fe3+@SA-PTX in different intermolecular forces destructive media. n.s. (No Significance) P > 0.05, *p