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Mitochondria play an important role in genesis and development of tumor, and are also drug targets. Herein, we developed a multifunctional celastrol (cela) nanoparticles with a positive core and a negative outer layer. Firstly, the mitochondrial targeted material: triphenyl phosphonium-tocopherol polyethylene glycol succinate (TPP-TPGS, TT) was synthesized, and prepared TT/PLGA@cela nanoparticles (NPs). Then, the positive charge on the surface was neutralized using tumor targeted and pH sensitive chondroitin sulfate-folic acid (CS-FA) material to obtain CS-FA/TT/PLGA@cela NPs. Characterization revealed CS-FA/TT/PLGA@cela NPs to be globular particles with smooth surfaces and an average diameter of 100 nm. This construct could improve the uptake in 4T1 cells. After CS-FA/TT/PLGA@cela NPs entered cancer cells, CS-FA was degraded, then the positively charged TT/PLGA@cela NPs were exposed and completed lysosomal escape, finally localizing to mitochondria. Subsequently, in the alkaline environment of mitochondria, cela is released to kill cancer cells. Meanwhile, the results of the mitochondrial respiration test and mitochondrial membrane potential assay demonstrated that CS-FA/TT/PLGA@cela NPs exerted mitochondrial injury and damage. Moreover, the NPs remarkably enhanced proapoptotic protein expression in 4T1 cells. Importantly, this nanoplatform was able to achieve excellent anti-cancer effects in vivo. Together, the results indicated that the mitochondria-targeting CS-FA/TT/PLGA@cela NPs potentially represent a signifcant advancement in breast cancer treatment.