The results showed that the dual‐drug anti‐glioma effect of lipid‐targeted alternative delivery NP systems (Tf‐PTX‐LNPs) of transferrin receptor (TfR)‐based PTX and the proapoptotic drug HePc significantly overcame O6‐methylguanine‐DNA methyltransferase‐induced resistance, and improve the therapeutic efficacy of GBM. This evidence concerns the gene TFRC and central nervous system cancer.