Skip to main content
SpringerLink
Log in

Lysosomal escaped protein nanocarriers for nuclear-targeted siRNA delivery

  • Research Paper
  • Published:
Analytical and Bioanalytical Chemistry Aims and scope Submit manuscript

Abstract

In the process of drug carrier design, lysosome degradation in cells is often neglected, which makes a considerable number of drugs not play a role. Here, we have constructed a tumor treatment platform (Apn/siRNA/NLS/HA/Apt) with unique lysosomal escape function and excellent cancer treatment effect. Apoferritin (Apn) has attracted more and more attention because of its high uniformity, modifiability, and controllability. Meanwhile, its endogenous nature can avoid the risk of immune response being eliminated. We used aptamer modified iron deficient protein nanocages (Apn) to tightly encapsulate the combination of siRNA and NLS (siRNA/NLS) with influenza virus hemagglutinin (HA peptide). After Apn/siRNA/NLS/HA/Apt was targeted into cells, the acidic environment of lysosome led to the cleavage of Apn nanocages, and the release of siRNA/NLS and HA peptide. HA peptide can destroy lysosome membrane, make siRNA/NLS escape lysosome, and enter the nucleus under the action of NLS, resulting in efficient gene silencing effect. This kind of cancer treatment strategy based on Apn nanocage shows high biocompatibility and unique lysosome escape property, which significantly improves the drug delivery and treatment efficiency.

Graphical abstract

Lysosomal escape protein nanocarriers for nuclear-targeted siRNA delivery

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Egeblad M, Nakasone ES, Werb Z. Tumors as organs: complex tissues that interface with the entire organism. Dev Cell. 2010;18:884–901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wang L, Wang Y, Hao J, Dong S. Magnetic fuller-ene-DNA/hyaluronic acid nanovehicles with magnetism/reduction dual-responsive triggered release. Biomacromolecules. 2017;18:1029–38.

    Article  CAS  PubMed  Google Scholar 

  3. Li N, Xiang M, Liu J, Tang H, Jiang J. DNA polymer nanoparticles programmed via supersandwich hybridization for imaging and therapy of cancer cells. Anal Chem. 2018;90:12951–8.

    Article  CAS  PubMed  Google Scholar 

  4. Moosavian SA, Abnous K, Akhtari J, Arabi L, Dewin AJ, Jafari M. 5TR1 aptamer-PEGylated liposomal doxorubicin enhances cellular uptake and suppresses tumour growth by targeting MUC1 on the surface of cancer cells. Artif Cell Nanomed B. 2018;46:2054–65.

    CAS  Google Scholar 

  5. Kong F, Zhang H, Qu X, Zhang X, Chen D, Ding R, et al. Gold nanorods, DNA origami, and porous silicon nanoparticle-functionalized biocompatible double emulsion for ver-satile targeted therapeutics and antibody combination therapy. Adv Mater. 2016;28:10195–203.

    Article  CAS  PubMed  Google Scholar 

  6. Zhang K, Li Y, Liu J, Yang X, Xu Y, Shi J, et al. Y-shaped circular aptamer–DNAzyme conjugates for highly efficient in vivo gene silencing. CCS Chem. 2020;2:631–41.

    Article  CAS  Google Scholar 

  7. Zhang K, Gao H, Deng R, Li J. Emerging applications of nanotechnology for controlling cell-surface receptor clustering. Angew Chem Int Ed. 2019;58:4790–9.

  8. Yata T, Takahashi Y, Tan M, Nakatsuji H, Ohtsuki S, Murakami T, et al. DNA nano-technology-based composite-type gold nanoparticle-immunostimulatory DNA hydrogel for tumor photothermal immunotherapy. Biomaterials. 2017;146:136–45.

    Article  CAS  PubMed  Google Scholar 

  9. Vellampatti S, Chandrasekaran G, Mitta SB, Lakshmanan VK, Park SH. Metallo-curcumin-conjugated DNA complexes induces preferential prostate cancer cells cytotoxicity and pause growth of bacterial cells. Sci Rep. 2018;8:14929.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Palazzolo S, Hadla M, Spena CR, Caligiuri I, Rotondo R, Adeel M, et al. An effective multi-stage liposomal DNA origami nanosystem for in vivo cancer therapy. Cancers. 2019;11:1997.

    Article  CAS  PubMed Central  Google Scholar 

  11. He S, Fan W, Wu N, Zhu J, Miao Y, Miao X, et al. Lipid-based liquid crystalline nanoparticles facilitate cytosolic delivery of siRNA via structural transformation. Nano Lett. 2018;18:2411–9.

    Article  CAS  PubMed  Google Scholar 

  12. Yang J, Jiang Q, He L, Zhan P, Liu Q, Liu S, et al. Self-assembled double-bundle DNA tetrahedron for efficient antisense delivery. ACS Appl Mater Interfaces. 2018;10:23693–9.

    Article  CAS  PubMed  Google Scholar 

  13. Zhang K, Liu J, Song Q, Wang D, Shi J, Zhang H, et al. Multifunctional DNA nanoflowers for autophagy inhibition and enhanced antitumor chemotherapy. Chem J Chin U. 2020;7:1461–9.

    Google Scholar 

  14. Chen L, Yang C, Yan X. Liposome-coated persistent lumines-cence nanoparticles as luminescence trackable drug carrier for chemotherapy. Anal Chem. 2017;89:6936–9.

    Article  CAS  PubMed  Google Scholar 

  15. Yang T, Tang Y, Liu L, Lv X, Wang Q, Ke H, et al. Size-dependent Ag2S nanodots for second near-infrared fluorescence/photoacoustics imaging and simul-taneous photothermal therapy. ACS Nano. 2017;11:1848–57.

    Article  CAS  PubMed  Google Scholar 

  16. Yang T, Ke H, Wang Q, Tang Y, Deng Y, Yang H, et al. Bifunctional tellurium nanodots for photo-induced synergistic cancer therapy. ACS Nano. 2017;11:10012–24.

    Article  CAS  PubMed  Google Scholar 

  17. Huang J, Guo M, Ke H, Zong C, Ren B, Liu G, et al. Rational design and synthesis of γFe2O3@Au magnetic gold nanoflowers for efficient cancer theranostics. Adv Mater. 2015;27:5049–56.

    Article  CAS  PubMed  Google Scholar 

  18. Du B, Jia S, Wang Q, Ding X, Liu Y, Yao H, et al. A self-targeting, dual ROS/pH-responsive apoferritin nanocage for spatiotemporally controlled drug delivery to breast cancer. Biomacromolecules. 2018;19:1026–36.

    Article  CAS  PubMed  Google Scholar 

  19. Lin C, Yang S, Peng C, Shieh MJ. Panitumumab-conjugated and platinum-cored pH-sensitive apoferritin nanocages for colorectal cancer-targeted therapy. ACS Appl Mater Interfaces. 2018;10:6096–106.

    Article  CAS  PubMed  Google Scholar 

  20. Fan K, Jia X, Zhou M, Wang K, Conde J, He J, et al. Ferritin nanocarrier traverses the blood brain barrier and kills glioma. ACS Nano. 2018;12:4105–15.

    Article  CAS  PubMed  Google Scholar 

  21. Ghosh S, Mohapatra S, Thomas A, Bhunia D, Saha A, Das G, et al. Apoferritin nanocage delivers combination of microtubule and nucleus targeting anticancer drugs. ACS Appl Mater Interfaces. 2016;8:30824–32.

    Article  CAS  PubMed  Google Scholar 

  22. Dostalova S, Cern T, Hynek D, Koudelkova Z, Vaculovic T, Kopel P, et al. Site-directed conjugation of antibodies to apoferritin nanocarrier for targeted drug delivery to prostate cancer cells. ACS Appl Mater Interfaces. 2016;8:14430–41.

    Article  CAS  PubMed  Google Scholar 

  23. Rui Y, Pang B, Zhang J, Liu Y, Hu H, Liu Z, et al. Near-infrared light-activatable siRNA delivery by microcapsules for combined tumour therapy. Artif Cell Nanomed B. 2018;46:15–24.

    Article  CAS  Google Scholar 

  24. Rafael D, Gener P, Andrade F, Franzoso J, Montero S, Fernández Y, et al. AKT2 siRNA delivery with amphiphilic-based polymeric micelles show efficacy against cancer stem cells. Drug Deliv. 2018;25:961–72.

  25. Ryoo NK, Lee J, Lee H, Hong H, Kim H, Lee JB, et al. Therapeutic effects of a novel siRNA-based anti-VEGF (siVEGF) nanoball for the treatment of choroidal neovascularization. Nanoscale. 2017;9:15461–9.

    Article  CAS  PubMed  Google Scholar 

  26. Brock DJ, Kondow-McConaghy HM, Hager EC, Pellois JP. Endosomal escape and cytosolic penetration of macromolecules mediated by synthetic delivery agents. Bioconjug Chem. 2019;30:293–304.

    Article  CAS  PubMed  Google Scholar 

  27. Beaudoin S, Rondeau A, Martel O, Bonin MA, Van Lier JE, Leyton JV. ChAcNLS, a novel modification to antibody-conjugates permitting target cell-specific endosomal escape, localization to the nucleus, and enhanced total intracellular accumulation. Mol Pharm. 2016;13:1915–26.

    Article  CAS  PubMed  Google Scholar 

  28. Xu Y, Zheng Y, Wu L, Zhu X, Zhang ZR, Huang Y. Novel solid lipid nanoparticle with endosomal escape function for oral delivery of insulin. ACS Appl Mater Interfaces. 2018;10:9315–24.

    Article  CAS  PubMed  Google Scholar 

  29. Ren X, Zhang K, Deng R, Li J. RNA splicing analysis: from in vitro testing to single-cell imaging. Chem. 2019;10:2571–92.

    Article  Google Scholar 

  30. Li J, Zheng C, Cansiz S, Wu C, Xu J, Cui C, et al. Self-assembly of DNA nanohydrogels with controllable size and stimuli-responsive property for targeted gene regulation therapy. J Am Chem Soc. 2015;137:1412–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yoshizumi T, Oikawa K, Chuah JA, Kodama Y, Numata K. Selective gene delivery for integrating exogenous DNA into plastid and mitochondrial genomes using peptide−DNA complexes. Biomacromolecules. 2018;19:1582–91.

    Article  CAS  PubMed  Google Scholar 

  32. Sun D, Sun Z, Jiang H, Vaidya AM, Xin R, Ayat NR, et al. Synthesis and evaluation of pH-sensitive multifunctional lipids for efficient delivery of CRISPR/Cas9 in gene editing. Bioconjug Chem. 2019;30:667–78.

    Article  CAS  PubMed  Google Scholar 

  33. Pan Q, Nie C, Hu Y, Yi J, Liu C, Zhang J, et al. Aptamer-functionalized DNA origami for targeted codelivery of antisense oligonucleotides and doxorubicin to enhance therapy in drug-resistant cancer cells. ACS Appl Mater Interfaces. 2020;12:400–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Shandong University Youth Science and Technology Plan(2020KJC003) and Epidemic Prevention and Control Emergency Special Project of Linyi University (2020YJKY003).

Author information

Author notes

  1. Xiuping Cao and Xinxin Shang contributed equally to this work.

Authors and Affiliations

  1. Collaborative Innovation Center of Tumor Marker Detection Technology, Equipment and Diagnosis-Therapy Integration in Universities of Shandong, Shandong Province Key Laboratory of Detection Technology for Tumor Markers, School of Chemistry and Chemical Engineering, Linyi University, Linyi, 276005, China

    Xiuping Cao, Xinxin Shang, Yingshu Guo, Xiaofei Zheng, Wenxin Li, Di Wu, Li Sun & Shanliang Mu

  2. Shandong Provincial Key Laboratory of Molecular Engineering, School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, China

    Xiuping Cao, Xinxin Shang & Yingshu Guo

  3. Shandong University of Political Science and Law, Jinan, 250014, China

    Chuanen Guo

Authors
  1. Xiuping Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xinxin Shang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yingshu Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaofei Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wenxin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Di Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Li Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shanliang Mu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chuanen Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yingshu Guo.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

ESM 1

(PDF 372 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cao, X., Shang, X., Guo, Y. et al. Lysosomal escaped protein nanocarriers for nuclear-targeted siRNA delivery. Anal Bioanal Chem 413, 3493–3499 (2021). https://doi.org/10.1007/s00216-021-03297-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00216-021-03297-5

Keywords

Search

Navigation