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ABSTRACT Cancer therapies often have narrow therapeutic indexes and involve potentially suboptimal combinations due to the dissimilar physical properties of drug molecules. Nanomedicine

platforms could address these challenges, but it remains unclear whether synergistic free-drug ratios translate to nanocarriers and whether nanocarriers with multiple drugs outperform

mixtures of single-drug nanocarriers at the same dose. Here we report a bottlebrush prodrug (BPD) platform designed to answer these questions in the context of multiple myeloma therapy. We

show that proteasome inhibitor (bortezomib)-based BPD monotherapy slows tumour progression in vivo and that mixtures of bortezomib, pomalidomide and dexamethasone BPDs exhibit in vitro

synergistic, additive or antagonistic patterns distinct from their corresponding free-drug counterparts. BPDs carrying a statistical mixture of three drugs in a synergistic ratio outperform

the free-drug combination at the same ratio as well as a mixture of single-drug BPDs in the same ratio. Our results address unanswered questions in the field of nanomedicine, offering design

principles for combination nanomedicines and strategies for improving current front-line monotherapies and combination therapies for multiple myeloma. Access through your institution Buy or

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NANOMEDICINE Article Open access 15 May 2025 BCMA-TARGETED BORTEZOMIB NANOTHERAPY IMPROVES THERAPEUTIC EFFICACY, OVERCOMES RESISTANCE, AND MODULATES THE IMMUNE MICROENVIRONMENT IN MULTIPLE

MYELOMA Article Open access 11 December 2023 IN VITRO AND EX VIVO ANTI-MYELOMA EFFECTS OF NANOCOMPOSITE AS4S4/ZNS/FE3O4 Article Open access 26 October 2022 DATA AVAILABILITY All data

supporting the findings of this study are available within the Article and its Supplementary Information and can also be obtained from the corresponding authors upon reasonable request.

CHANGE HISTORY * _ 11 JUNE 2024 Editor’s Note: The Editorial team is currently investigating questions raised about the fluorescence images in Figs 3 and 5 presented in the Article. We will

update readers once we have further information and all parties have been given an opportunity to respond in full. _ * _ 13 MARCH 2023 A Correction to this paper has been published:

https://doi.org/10.1038/s41565-023-01345-y _ * _ 10 AUGUST 2023 A Correction to this paper has been published: https://doi.org/10.1038/s41565-023-01499-9 _ REFERENCES * Tibbitt, M. W.,

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delivery. _Nat. Rev. Drug Discov._20, 101–124 (2021). Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS We thank the NIH-NCI (1R01CA220468-01 (J.A.J., P.P.G.) and

R01CA205954 (I.M.G.)), the Leukemia and Lymphoma Society and the National Science Foundation (Graduate Research Fellowship (H.V.-T.N.)) for supporting this research. This work was further

supported in part by the Koch Institute Core Grant P30-CA14051 from the NCI. A.D. acknowledges support from the International Myeloma Foundation, the Fondation Française pour la Recherche

contre le Myélome et les Gammapathies (FFRMG) and Inserm Cancer. A.D., J.A.J. and I.M.G. acknowledge support from the Stand Up to Cancer Dream Team Multiple Myeloma grant. P.P.G.

acknowledges the generous support of the Charles W. and Jennifer C. Johnson Clinical Investigator Fund as well as the Kathryn Fox Samway Foundation. AUTHOR INFORMATION Author notes * These

authors contributed equally: Alexandre Detappe, Hung V.-T. Nguyen. AUTHORS AND AFFILIATIONS * Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Alexandre Detappe,

 Hung V.-T. Nguyen, Michael P. Agius, Clelia Mathieu, Nang K. Su, Irene M. Ghobrial & P. Peter Ghoroghchian * Harvard Medical School, Boston, MA, USA Alexandre Detappe, Hung V.-T.

Nguyen, Michael P. Agius, Clelia Mathieu, Nang K. Su, Irene M. Ghobrial & P. Peter Ghoroghchian * Institut de Cancérologie Strasbourg Europe, Strasbourg, France Alexandre Detappe *

Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA Hung V.-T. Nguyen, Yivan Jiang, Wencong Wang, Samantha L. Kristufek & Jeremiah A. Johnson * Window

Therapeutics, Boston, MA, USA Hung V.-T. Nguyen & Yivan Jiang * Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA David J. Lundberg & 

Sachin Bhagchandani * Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA Jeremiah A. Johnson * Broad Institute of MIT and Harvard,

Cambridge, MA, USA Jeremiah A. Johnson Authors * Alexandre Detappe View author publications You can also search for this author inPubMed Google Scholar * Hung V.-T. Nguyen View author

publications You can also search for this author inPubMed Google Scholar * Yivan Jiang View author publications You can also search for this author inPubMed Google Scholar * Michael P. Agius

View author publications You can also search for this author inPubMed Google Scholar * Wencong Wang View author publications You can also search for this author inPubMed Google Scholar *

Clelia Mathieu View author publications You can also search for this author inPubMed Google Scholar * Nang K. Su View author publications You can also search for this author inPubMed Google

Scholar * Samantha L. Kristufek View author publications You can also search for this author inPubMed Google Scholar * David J. Lundberg View author publications You can also search for this

author inPubMed Google Scholar * Sachin Bhagchandani View author publications You can also search for this author inPubMed Google Scholar * Irene M. Ghobrial View author publications You

can also search for this author inPubMed Google Scholar * P. Peter Ghoroghchian View author publications You can also search for this author inPubMed Google Scholar * Jeremiah A. Johnson

View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS J.A.J., P.P.G., I.M.G., A.D. and H.V.-T.N. conceived the project idea. H.V.-T.N., Y.J.,

W.W. and S.L.K. synthesized and characterized the materials. A.D., M.P.A. and C.M. performed the biological experiments. D.J.L. performed the computational simulations. S.B. conducted the

cryogenic electron microscopy studies. All authors helped in analysing the results. J.A.J., P.P.G., I.M.G., A.D. and H.V.-T.N. wrote the paper. All authors read and edited the manuscript.

CORRESPONDING AUTHORS Correspondence to Irene M. Ghobrial, P. Peter Ghoroghchian or Jeremiah A. Johnson. ETHICS DECLARATIONS COMPETING INTERESTS A.D., H.V.-T.N., Y.J., I.M.G., P.P.G. and

J.A.J. are named inventors on a patent application (US patent application no. 16/825,269) jointly filed by the Massachusetts Institute of Technology and the Dana-Farber Cancer Institute on

the Btz macromolecular PIs described in this work. H.V.-T.N., Y.J. and J.A.J. are co-founders and shareholders of Window Therapeutics, which seeks to translate this technology to clinical

cancer therapies. The other authors declare no competing interests. PEER REVIEW PEER REVIEW INFORMATION _Nature Nanotechnology_ thanks Jo Caers, Twan Lammers and the other, anonymous,

reviewer(s) for their contribution to the peer review of this work. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published

maps and institutional affiliations. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION Supplementary Figs. 1–37, Tables 1 and 2, materials/general methods/instrumentation and synthesis

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applicable law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Detappe, A., Nguyen, H.VT., Jiang, Y. _et al._ Molecular bottlebrush prodrugs as mono- and triplex combination

therapies for multiple myeloma. _Nat. Nanotechnol._ 18, 184–192 (2023). https://doi.org/10.1038/s41565-022-01310-1 Download citation * Received: 26 February 2021 * Accepted: 06 December 2022

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