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Protease-Responsive Peptide-Conjugated Mitochondrial-Targeting AIEgens for Selective Imaging and Inhibition of SARS-CoV-2-Infected Cells

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    Protease-Responsive Peptide-Conjugated Mitochondrial-Targeting AIEgens for Selective Imaging and Inhibition of SARS-CoV-2-Infected Cells
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    • Yong Cheng
      Yong Cheng
      Department of NanoEngineering, University of California, San Diego, La Jolla, California 92093, United States
      More by Yong Cheng
    • Alex E. Clark
      Alex E. Clark
      Department of Medicine, University of California, San Diego, La Jolla, California 92093, United States
      More by Alex E. Clark
    • Jiajing Zhou
      Jiajing Zhou
      Department of NanoEngineering, University of California, San Diego, La Jolla, California 92093, United States
      More by Jiajing Zhou
      Orcidhttps://orcid.org/0000-0001-5203-4737
    • Tengyu He
      Tengyu He
      Materials Science and Engineering Program, University of California, San Diego, La Jolla, California 92093, United States
      More by Tengyu He
      Orcidhttps://orcid.org/0000-0002-6767-4849
    • Yi Li
      Yi Li
      Department of NanoEngineering, University of California, San Diego, La Jolla, California 92093, United States
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    • Raina M. Borum
      Raina M. Borum
      Department of NanoEngineering, University of California, San Diego, La Jolla, California 92093, United States
      More by Raina M. Borum
      Orcidhttps://orcid.org/0000-0003-4265-3109
    • Matthew N. Creyer
      Matthew N. Creyer
      Department of NanoEngineering, University of California, San Diego, La Jolla, California 92093, United States
      More by Matthew N. Creyer
      Orcidhttps://orcid.org/0000-0003-1213-8245
    • Ming Xu
      Ming Xu
      Department of NanoEngineering, University of California, San Diego, La Jolla, California 92093, United States
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    • Zhicheng Jin
      Zhicheng Jin
      Department of NanoEngineering, University of California, San Diego, La Jolla, California 92093, United States
      More by Zhicheng Jin
      Orcidhttps://orcid.org/0000-0001-6072-7533
    • Jingcheng Zhou
      Jingcheng Zhou
      Department of NanoEngineering, University of California, San Diego, La Jolla, California 92093, United States
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    • Wonjun Yim
      Wonjun Yim
      Materials Science and Engineering Program, University of California, San Diego, La Jolla, California 92093, United States
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      Orcidhttps://orcid.org/0000-0002-0242-7898
    • Zhuohong Wu
      Zhuohong Wu
      Department of NanoEngineering, University of California, San Diego, La Jolla, California 92093, United States
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    • Pavla Fajtová
      Pavla Fajtová
      Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, United States
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    • Anthony J. O’Donoghue
      Anthony J. O’Donoghue
      Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, United States
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    • Aaron F. Carlin
      Aaron F. Carlin
      Department of Medicine, University of California, San Diego, La Jolla, California 92093, United States
      Department of Pathology, University of California, San Diego, La Jolla, California 92093, United States
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    • Jesse V. Jokerst*
      Jesse V. Jokerst
      Department of NanoEngineering, University of California, San Diego, La Jolla, California 92093, United States
      Materials Science and Engineering Program, University of California, San Diego, La Jolla, California 92093, United States
      Department of Radiology, University of California, San Diego, La Jolla, California 92093, United States
      *Email: [email protected]
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    Other Access OptionsSupporting Information (5)

    ACS Nano

    Cite this: ACS Nano 2022, 16, 8, 12305–12317
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsnano.2c03219
    Published July 25, 2022
    Copyright © 2022 American Chemical Society
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    Abstract

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    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a serious threat to human health and lacks an effective treatment. There is an urgent need for both real-time tracking and precise treatment of the SARS-CoV-2-infected cells to mitigate and ultimately prevent viral transmission. However, selective triggering and tracking of the therapeutic process in the infected cells remains challenging. Here, we report a main protease (Mpro)-responsive, mitochondrial-targeting, and modular-peptide-conjugated probe (PSGMR) for selective imaging and inhibition of SARS-CoV-2-infected cells via enzyme-instructed self-assembly and aggregation-induced emission (AIE) effect. The amphiphilic PSGMR was constructed with tunable structure and responsive efficiency and validated with recombinant proteins, cells transfected with Mpro plasmid or infected by SARS-CoV-2, and a Mpro inhibitor. By rational construction of AIE luminogen (AIEgen) with modular peptides and Mpro, we verified that the cleavage of PSGMR yielded gradual aggregation with bright fluorescence and enhanced cytotoxicity to induce mitochondrial interference of the infected cells. This strategy may have value for selective detection and treatment of SARS-CoV-2-infected cells.

    Copyright © 2022 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.2c03219.

    • Movie S1: SARS-CoV-2 infected TMPRSS2-Vero cells incubated with PSGMR, Hoechst 33258, PI, and Alexa 488 for nucleocapsid (turn around X-axis) (AVI)

    • Movie S2: SARS-CoV-2 infected TMPRSS2-Vero cells incubated with PSGMR, Hoechst 33258, PI, and Alexa 488 for nucleocapsid (Z-axis scanning) (AVI)

    • Movie S3: SARS-CoV-2 infected TMPRSS2-Vero cells incubated with PSGMR, Hoechst 33258, PI, and Alexa 488 for Mpro (Turn around X-axis) (AVI)

    • Movie S4: SARS-CoV-2 infected TMPRSS2-Vero cells incubated with PSGMR, Hoechst 33258, PI, and Alexa 488 for Mpro (Z-axis scanning) (AVI)

    • Schemes S1–S5, Table S1, and Figures S1–S44; molecular design, imaging mechanism, and Mpro peptide sequence; peptide sequences used in this study; synthesis and characterization of PSGMR, PSMR, and PMR; synthetic route, ESI-MS, HR-MS, and HPLC results of PSGMR, PSMR, and PMR; time-dependent fluorescence spectra of PSGMR, PSMR, and PMR incubation with Mpro; CMC, TEM images, and hydrodynamic size results of different concentrations of PSGMR and PMR incubation with Mpro; CLSM images, Z-stack images, Pearson correlation coefficient of colocalization, and flow cytometric results of HeLa cells, plasmid-transfected HEK 293T cells, TMPRSS2-Vero cells, and SARS-CoV-2-infected TMPRSS2-Vero cells incubated with PyTPE, PSGMR, PMR, Hoechst 33258, Alexa 488, and PI (PDF)

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    Cited By

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    This article is cited by 33 publications.

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    ACS Nano

    Cite this: ACS Nano 2022, 16, 8, 12305–12317
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsnano.2c03219
    Published July 25, 2022
    Copyright © 2022 American Chemical Society
    Request reuse permissions

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