Lung cancer continues to be the leading cause of mortality globally. Nanotechnology-mediated targeted drug delivery approach is one of the promising strategies for the treatment of lung cancer. Due to their multifactorial role, mesoporous silica nanoparticles (MSNs), have attracted a lot of attention for drug delivery. The emerging dual-drug co-delivery approach has drawn much attention due to circumventing various drug-resistant mechanisms in tumor cells. Further, functionalization of si-RNA (survivin) to the dual drugs (etoposide plus carfilzomib) or (docetaxel plus carfilzomib) loaded MSNs can be a potential tool to inhibit gene expression specifically. In the present study, we investigated the comparative therapeutic efficacy of co-delivered anticancer drugs functionalized with survivin siRNA in MSNs for lung cancer. According to our findings, this kind of combination therapy has inhibited the function of the survivin protein while promoting increased therapeutic efficacy due to synergistic pharmacological activity, and found si-RNA- (etoposide plus carfilzomib) to be a better candidate for lung cancer treatment in the future.