以奈米載體攜帶小分子藥物，可提升小分子抗癌藥物面對健康細胞與癌細胞的區別力，並維持處於生理環境中的溶解度和穩定性，以及避免出現在抗藥性癌細胞中的多重藥物輸出幫浦蛋白，將位於細胞內藥物排出干擾藥物使用效率。目前DNA連接型金奈米粒子為廣泛探索的藥物攜帶載體之一，歸因於DNA的雙股螺旋結構可鑲嵌入特定類型抗癌藥物，doxorubicin (DOX)則為其中一類，以及金奈米粒子可接收近紅外光激發產生光熱效應，促使DNA解旋釋放DOX，完成遠端遙控藥物釋放操作。連接於金奈米粒子外部的DNA，屬於帶有未修飾CpG雙核甘酸的人工合成去氧核糖核苷酸(ODN)，當暴露於生理環境中，容易遭受輻射、核酸酶攻擊導致結構受損，或是活化Toll-like receptor (TLR) 9啟動免疫反應風暴。為了改善外露DNA可能導致的風險，我們設計了一非抗原性質體DNA封裝型金奈米膠囊，此金奈米膠囊可保護包裹於內部的質體DNA，免除外界環境擾動和免疫系統追蹤，同時具備優秀藥物裝載量，且能依照需求以紅外光遙控釋放藥物的時機，確保治療抗藥性癌細胞的效率及安全性。

Nanocarriers have been designed as a drug delivery platform to overcome concerns of conventional small molecular anticancer drugs, such as non-specific exposure to healthy cells, limited solubility and stability in physiological conditions, and pumping out condition by multidrug resistance transporter overexpressed in drug resistant cancer cells. Recently, growing research efforts led to the development of the DNA-gold combined nanocarriers based on the nature of the ability of photothermal effect in gold nanoparticles to perform NIR-responsive remote control drug release by unwinding hydrogen bonded double-helical DNA. Moreover, complimentary strands of DNA could structurally intercalate with several anti-cancer therapeutics such as doxorubicin (DOX). However, the exposure of synthetic oligodeoxyribonucleotides (ODN) with unmodified CpG dinucleotide modified on the surface of gold nanoparticles in biological environment allows radical or nuclease attack, and may active Toll-like receptor (TLR) 9 and stimulate the immune response liable to modulation disorder. Herein we design a plasmid DNA encapsulated gold nanocapsule that can protect plasmid DNA from aggressive environmental conditions and evade immune system tracking. With high payload of anticancer drug, the immunogen-free nanocapsule is a reliable delivery vehicle that guarantees the efficiency and safety of targeted NIR-responsive controlled release for drug resistant cancer.

1. Li, Z., Tan, S., Li, S., Shen, Q. and Wang, K. (2017). Cancer drug delivery in the nano era: An overview and perspectives. Oncology Reports, 38(2), pp.611-624.
2. Knop, K., Hoogenboom, R., Fischer, D., & Schubert, U. (2010). ChemInform Abstract: Poly(ethylene glycol) in Drug Delivery: Pros and Cons as Well as Potential Alternatives. Cheminform, 42(3), 6288 – 6308. doi: 10.1002/chin.201103264
3. Lee, J., & Nan, A. (2012). Combination Drug Delivery Approaches in Metastatic Breast Cancer. Journal Of Drug Delivery, 2012, 1-17. doi: 10.1155/2012/915375
4. Willets, K., & Van Duyne, R. (2007). Localized Surface Plasmon Resonance Spectroscopy and Sensing. Annual Review Of Physical Chemistry, 58(1), 267-297. doi: 10.1146/annurev.physchem.58.032806.104607
5. Webb, J., & Bardhan, R. (2014). Emerging advances in nanomedicine with engineered gold nanostructures. Nanoscale, 6(5), 2502. doi: 10.1039/c3nr05112a
6. Jaque, D., Martínez Maestro, L., del Rosal, B., Haro-Gonzalez, P., Benayas, A., & Plaza, J. et al. (2014). Nanoparticles for photothermal therapies. Nanoscale, 6(16), 9494-9530. doi: 10.1039/c4nr00708e
7. Song, J., Yang, X., Yang, Z., Lin, L., Liu, Y., & Zhou, Z. et al. (2017). Rational Design of Branched Nanoporous Gold Nanoshells with Enhanced Physico-Optical Properties for Optical Imaging and Cancer Therapy. ACS Nano, 11(6), 6102-6113. doi: 10.1021/acsnano.7b02048
8. Smith, A., Mancini, M., & Nie, S. (2009). Second window for in vivo imaging. Nature Nanotechnology, 4(11), 710-711. doi: 10.1038/nnano.2009.326
9. Choma, J., Dziura, A., Jamioła, D., Nyga, P., & Jaroniec, M. (2011). Preparation and properties of silica–gold core–shell particles. Colloids And Surfaces A: Physicochemical And Engineering Aspects, 373(1-3), 167-171. doi: 10.1016/j.colsurfa.2010.10.046
10. Hirsch, L., Gobin, A., Lowery, A., Tam, F., Drezek, R., Halas, N., & West, J. (2006). Metal Nanoshells. Annals Of Biomedical Engineering, 34(1), 15-22. doi: 10.1007/s10439-005-9001-8
11. Zhang, Q., Zhang, T., Ge, J., & Yin, Y. (2008). Permeable Silica Shell through Surface-Protected Etching. Nano Letters, 8(9), 2867-2871. doi: 10.1021/nl8016187
12. Liu, S., & Han, M. (2009). Silica-Coated Metal Nanoparticles. Chemistry - An Asian Journal, 36 – 45. doi: 10.1002/asia.200900228
13. Prodan, E. (2003). A Hybridization Model for the Plasmon Response of Complex Nanostructures. Science, 302(5644), 419-422. doi: 10.1126/science.1089171
14. Khanadeev, V., Khlebtsov, B., & Khlebtsov, N. (2017). Optical properties of gold nanoshells on monodisperse silica cores: Experiment and simulations. Journal Of Quantitative Spectroscopy And Radiative Transfer, 187, 1-9. doi: 10.1016/j.jqsrt.2016.09.004
15. West, J., & Halas, N. (2003). Engineered Nanomaterials for Biophotonics Applications: Improving Sensing, Imaging, and Therapeutics. Annual Review Of Biomedical Engineering, 5(1), 285-292. doi: 10.1146/annurev.bioeng.5.011303.120723
16. Huang, X., & El-Sayed, M. (2010). Gold nanoparticles: Optical properties and implementations in cancer diagnosis and photothermal therapy. Journal Of Advanced Research, 1(1), 13-28. doi: 10.1016/j.jare.2010.02.002
17. You, J., Zhang, G., & Li, C. (2010). Exceptionally High Payload of Doxorubicin in Hollow Gold Nanospheres for Near-Infrared Light-Triggered Drug Release. ACS Nano, 4(2), 1033-1041. doi: 10.1021/nn901181c
18. Agudelo, D., Bourassa, P., Bérubé, G., & Tajmir-Riahi, H. (2014). Intercalation of antitumor drug doxorubicin and its analogue by DNA duplex: Structural features and biological implications. International Journal Of Biological Macromolecules, 66, 144-150. doi: 10.1016/j.ijbiomac.2014.02.028
19. Pérez-Arnaiz, C., Busto, N., Leal, J., & García, B. (2014). New Insights into the Mechanism of the DNA/Doxorubicin Interaction. The Journal Of Physical Chemistry B, 118(5), 1288-1295. doi: 10.1021/jp411429g
20. Yang, X. (1999). Structural studies of atom-specific anticancer drugs acting on DNA. Pharmacology & Therapeutics, 83(3), 181-215. doi: 10.1016/s0163-7258(99)00020-0
21. Juliano, R. (2016). The delivery of therapeutic oligonucleotides. Nucleic Acids Research, 44(14), 6518-6548. doi: 10.1093/nar/gkw236
22. Xiao, Z., Ji, C., Shi, J., Pridgen, E., Frieder, J., Wu, J., & Farokhzad, O. (2012). DNA Self-Assembly of Targeted Near-Infrared-Responsive Gold Nanoparticles for Cancer Thermo-Chemotherapy. Angewandte Chemie International Edition, 51(47), 11853-11857. doi: 10.1002/anie.201204018
23. Alexander, C., Maye, M., & Dabrowiak, J. (2011). DNA-capped nanoparticles designed for doxorubicin drug delivery. Chemical Communications, 47(12), 3418. doi: 10.1039/c0cc04916f
24. Zagorovsky, K., Chou, L., & Chan, W. (2016). Controlling DNA–nanoparticle serum interactions. Proceedings Of The National Academy Of Sciences, 113(48), 13600-13605. doi: 10.1073/pnas.1610028113
25. Poon, L., Zandberg, W., Hsiao, D., Erno, Z., Sen, D., Gates, B., & Branda, N. (2010). Photothermal Release of Single-Stranded DNA from the Surface of Gold Nanoparticles Through Controlled Denaturating and Au−S Bond Breaking. ACS Nano, 4(11), 6395-6403. doi: 10.1021/nn1016346
26. Wang, C., Du, Y., Wu, Q., Xuan, S., Zhou, J., & Song, J. et al. (2013). Stimuli-responsive plasmonic core–satellite assemblies: i-motif DNA linker enabled intracellular pH sensing. Chemical Communications, 49(51), 5739. doi: 10.1039/c3cc80005a
27. Raeesi, V., Chou, L., & Chan, W. (2016). Tuning the Drug Loading and Release of DNA-Assembled Gold-Nanorod Superstructures. Advanced Materials, 28(38), 8511-8518. doi: 10.1002/adma.201600773
28. Awino, J., Gudipati, S., Hartmann, A., Santiana, J., Cairns-Gibson, D., Gomez, N., & Rouge, J. (2017). Nucleic Acid Nanocapsules for Enzyme-Triggered Drug Release. Journal Of The American Chemical Society, 139(18), 6278-6281. doi: 10.1021/jacs.6b13087
29. Puddu, M., Paunescu, D., Stark, W., & Grass, R. (2014). Magnetically Recoverable, Thermostable, Hydrophobic DNA/Silica Encapsulates and Their Application as Invisible Oil Tags. ACS Nano, 8(3), 2677-2685. doi: 10.1021/nn4063853
30. Paunescu, D., Fuhrer, R., & Grass, R. (2013). Protection and Deprotection of DNA-High-Temperature Stability of Nucleic Acid Barcodes for Polymer Labeling. Angewandte Chemie International Edition, 52(15), 4269-4272. doi: 10.1002/anie.201208135
31. Paunescu, D., Puddu, M., Soellner, J., Stoessel, P., & Grass, R. (2013). Reversible DNA encapsulation in silica to produce ROS-resistant and heat-resistant synthetic DNA 'fossils'. Nature Protocols, 8(12), 2440-2448. doi: 10.1038/nprot.2013.154
32. Chinnathambi, S., Chen, S., Ganesan, S., & Hanagata, N. (2012). Binding Mode of CpG Oligodeoxynucleotides to Nanoparticles Regulates Bifurcated Cytokine induction via Toll-like Receptor 9. Scientific Reports, 2(1). doi: 10.1038/srep00534
33. Takeuchi, O., & Akira, S. (2010). Pattern Recognition Receptors and Inflammation. Cell, 140(6), 805-820. doi: 10.1016/j.cell.2010.01.022
34. O'Neill, L., Golenbock, D., & Bowie, A. (2013). The history of Toll-like receptors — redefining innate immunity. Nature Reviews Immunology, 13(6), 453-460. doi: 10.1038/nri3446
35. Klinman, D. (2004). Immunotherapeutic uses of CpG oligodeoxynucleotides. Nature Reviews Immunology, 4(4), 249-259. doi: 10.1038/nri1329
36. Pohar, J., Lainšček, D., Ivičak-Kocjan, K., Cajnko, M., Jerala, R., & Benčina, M. (2017). Short single-stranded DNA degradation products augment the activation of Toll-like receptor 9. Nature Communications, 8, 15363. doi: 10.1038/ncomms15363
37. Gao, W., Xiong, Y., Li, Q., & Yang, H. (2017). Inhibition of Toll-Like Receptor Signaling as a Promising Therapy for Inflammatory Diseases: A Journey from Molecular to Nano Therapeutics. Frontiers In Physiology, 8. doi: 10.3389/fphys.2017.00508
38. Anuradha, J., Abbasi, T., & Abbasi, S. (2015). An eco-friendly method of synthesizing gold nanoparticles using an otherwise worthless weed pistia (Pistia stratiotes L.). Journal Of Advanced Research, 6(5), 711-720. doi: 10.1016/j.jare.2014.03.006
39. Asadi Asadabad, M., & Jafari Eskandari, M. (2014). Transmission Electron Microscopy as Best Technique for Characterization in Nanotechnology. Synthesis And Reactivity In Inorganic, Metal-Organic, And Nano-Metal Chemistry, 45(3), 323-326. doi: 10.1080/15533174.2013.831901
40. Thirugnanam, T. (2013). Effect of Polymers (PEG and PVP) on Sol-Gel Synthesis of Microsized Zinc Oxide. Journal Of Nanomaterials, 2013, 1-7. doi: 10.1155/2013/362175
41. Salman, A., Sebbag, G., Argov, S., Mordechai, S., & Sahu, R. (2015). Early detection of colorectal cancer relapse by infrared spectroscopy in “normal” anastomosis tissue. Journal Of Biomedical Optics, 20(7), 075007. doi: 10.1117/1.jbo.20.7.075007
42. Huang, C., Bao, Q., Hunting, D., Zheng, Y., & Sanche, L. (2013). Conformation-Dependent DNA Damage Induced by Gold Nanoparticles. Journal Of Biomedical Nanotechnology, 9(5), 856-862. doi: 10.1166/jbn.2013.1578
43. Ackerson, C., Sykes, M., & Kornberg, R. (2005). Defined DNA/nanoparticle conjugates. Proceedings Of The National Academy Of Sciences, 102(38), 13383-13385. doi: 10.1073/pnas.0506290102
44. F. Jiao, P., Y. Zhou, H., X. Chen, L., & Yan, B. (2011). Cancer-Targeting Multifunctionalized Gold Nanoparticles in Imaging and Therapy. Current Medicinal Chemistry, 18(14), 2086-2102. doi: 10.2174/092986711795656199
45. Puddu, M., Paunescu, D., Stark, W., & Grass, R. (2014). Magnetically Recoverable, Thermostable, Hydrophobic DNA/Silica Encapsulates and Their Application as Invisible Oil Tags. ACS Nano, 8(3), 2677-2685. doi: 10.1021/nn4063853