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Conventional cancer combination therapy usually involves systemic delivery of anticancer drugs which may lead to the destruction of normal cells and physiological toxicity due to the lack of targeting ability and toxicity of drug carriers. In the present study, a triple combination nanosystem of gene therapy, chemotherapy and phototherapy delivered by multifunctional RNA nanohydrogels (RNA NHs) was established. By taking the advantages of DNA nanotechnology and rolling circle transcription (RCT), three lung cancer inhibitor microRNA (let-7a, microRNA 34a, microRNA 145) hairpins were integrated in one RNA NH nanoparticle, leading to the simultaneous silencing of three targeted mRNAs. Meanwhile, RNA NH carried doxorubicin (DOX, a chemotherapy drug) as well as 5,10,15,20-tetrakis (1-methylpyridinium-4-yl) porphyrin (TMPyP4, a photosensitizer) and delivered these drugs to cancer cells. It was demonstrated that lung cancer inhibitor microRNAs integrated in RNA NHs, DOX and TMPyP4 could play a synergistic anti-cancer role in multi-drug resistance cancer cells. Under the action of aptamer sequence S6 that was modified with cholesterol, the resulting RNA NHs were condensed to feasible size without the assistance of polyelectrolyte condensation reagents and showed cancer-specific cellular targeting. Subsequently, thousands of copies of miRNA together with chemotherapy drug as well as photosensitizer were delivered to cancer cells specifically, and an ideal synergistic treatment effect was achieved in vivo, thus playing a combined role of gene therapy, chemotherapy and phototherapy. Through this study, it can be concluded that the triple combination therapy nanosystem can overcome the multidrug resistance caused by the malfunction of genes in chemotherapy and shows a great potential in the field of multifunctional synergistic cancer treatment.

We describe an implementation of the cluster-in-molecule (CIM) resolution of the identity (RI) approximation second-order Møller-Plesset perturbation theory (CIM-RI-MP2), with the purpose of extending RI-MP2 calculations to very large systems. For typical conformers of several large polypeptides, we calculated their conformational energy differences with the CIM-RI-MP2 and the generalized energy-based fragmentation MP2 (GEBF-MP2) methods, and compared these results with the density functional theory (DFT) results obtained with several popular functionals. Our calculations show that the conformational energy differences obtained with CIM-RI-MP2 and GEBF-MP2 are very close to each other. In comparison with the GEBF-MP2 and CIM-RI-MP2 relative energies, we found that the DFT functionals (CAM-B3LYP-D3, LC-ωPBE-D3, M05-2X, M06-2X and ωB97XD) can give quite accurate conformational energy differences for structurally similar conformers, but provide less-accurate results for structurally very different conformers.