The combination of gene therapy and chemotherapy is emerging as a promising strategy for multidrug-resistant (MDR) cancer treatment. However, due to the significant differences in the physicochemical properties between macromolecular oligonucleotides and chemodrugs, the co-delivery of different drug combos makes for a great challenge. Moreover, the biosafety of the carriers and poor lysosomal escape of oligonucleotides are the main concerns for combination therapy. Herein, we developed a facile carrier-free strategy to co-deliver small interfering RNA (siRNA) and positive-charged chemodrugs (termed cationic amphiphilic chemodrugs, CACDs), in which CACDs interact with negative-charged anti P-glycoprotein siRNA (siPgp) without extra carriers and self-assemble into siPgp/CACDs nanoparticles (NPs[siPgp/CACDs]). Meanwhile, the CACDs also play an important role in the lysosomal escape of siRNA. Both molecular dynamics simulations and experimental characterization demonstrate that CACDs and siRNA can self-assemble into nanoparticles. Furthermore, red blood cell membrane (RBCm) was used to camouflage the NPs[siPgp/CACDs] to enhance their physiological stability and prolong the circulation time. Both in vitro and in vivo assessments reveal their excellent performance for drug-resistant cancer treatment. This strategy provides a safe and efficient pathway for gene and chemo combination therapy for MDR cancers.