Multidrug resistance (MDR) is one of the major obstacles in tumor treatment. Herein, we reported an active targeting strategy with peptide-mediated nanoparticles deep into tumor parenchyma, which iRGD conjugated d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) mediated codelivery of paclitaxel (PTX) and survivin shRNA (shSur) for the reversal of lung cancer resistance. Pluronic P85-polyethyleneimine/TPGS complex nanoparticles incorporated with iRGD-TPGS conjugate codelivering PTX and shSur systems (iPTPNs) could induce effective cellular uptake, RNAi effects, and cytotoxicity on A549 and A549/T cells. In particular, iPTPNs showed superiority in biodistribution, survivin expression, tumor apoptosis, and antitumor efficacy by simultaneously exerting an enhanced permeability and retention (EPR) effect and iRGD mediated active targeting effects. iPTPNs significantly enhanced the accumulation of PTX and shSur, down-regulated survivin expression, and induced cell apoptosis in tumor tissue. The in vivo antitumor efficacy showed the tumor volume of iPTPNs group (10 mg/kg) was only 12.7% of the Taxol group. Therefore, the iRGD mediated PTX and shSur codelivery system could be a very powerful approach for the reversal and therapy of lung cancer resistance.