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Conventional cancer chemotherapy is facing difficulties in improving the bioavailability, overcoming the severe adverse side effects of chemotherapeutics and reversing the multidrug resistance of cancer cells. To address these challenges, we report a feasible strategy to realize a multistage sustained release of dual drugs using injectable short nanofibers as a carrier system. In this work, layered double hydroxide (LDH) was selected as the primary carrier to load the anticancer drug doxorubicin (DOX), and the DOX-loaded LDH was incorporated within an α-tocopheryl succinate (α-TOS)-doped poly(lactic-co-glycolic acid) (PLGA) fibrous mat. After homogenization in the presence of poly(vinyl alcohol), dual drug-loaded injectable short nanofibers (DOX@LDH/α-TOS/PLGA) with an average length of 17.4 μm and a diameter of 830.2 nm were formed to have a pH-responsive drug release profile. In an acidic tumor microenvironment, DOX@LDH/α-TOS/PLGA short nanofibers show a fast release of α-TOS due to its incorporation within the fiber matrix and a slow release of DOX due to the extended diffusion distance (first from the LDH to the fiber matrix and then from the fiber matrix to the external medium). As α-TOS can inhibit the expression of p-glycoprotein on the cell membrane, the dual drug-loaded short nanofibers can exert the therapeutic effect on multidrug-resistant cancer cells in vitro. The developed injectable short nanofiber-based drug delivery system may be extended to the treatment of different tumor types in vivo, in particular for long-term effective chemotherapy of drug-resistant tumors. [ABSTRACT FROM AUTHOR]