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Spotlight Publication: “Potentiating cancer immunotherapies with modular albumin-hitchhiking nanobody–STING agonist conjugates” published in Nature Biomedical Engineering

Jan 20, 2026, 2:31 PM

a, Scheme depicting the concept of an albumin-hitchhiking nanobody–STING agonist conjugate for cancer immunotherapy. Anti-albumin nanobodies conjugated to STING agonists bind to circulating albumin in situ, resulting in improved pharmacokinetics and increased biodistribution to tumour sites that stimulates antitumour innate and adaptive immune responses. b, Computational model of the anti-albumin nanobody (nAlb) binding at domain IIB of HSA. c, ITC traces (top) and binding isotherms (bottom) of nAlb binding to human and mouse serum albumin at pH 7.5 with calculated dissociation constant (Kd). d, Reaction scheme for generating molecularly homogeneous nAlb conjugates through site-selective enzymatic ligation of an amine-PEG3-azide followed by conjugation of agonist or dye cargo through strain-promoted azide-alkyne cycloaddition (SPAAC). e, Structure of diABZI STING agonist conjugated to a DBCO-PEG11 handle for ligation to azide-functionalized nanobodies via SPAAC. f,g, ESI–MS (f) and SDS–PAGE (g) showing nanobody conjugate purity and molecular weight (see Source Data for uncropped gel in ref. 90). h,i, Dose–response curves in A549-Dual (n = 3) (h) and THP1-Dual type I interferon reporter cell lines (n = 3) (i) with estimated EC50 values indicated in the legends; RLU, relative light unit. j, qPCR analysis of gene expression in mouse BMDMs treated in vitro with 0.25 µM of free diABZI or nAlb–diABZI conjugate (n = 3). P values determined by one-way ANOVA with Dunnett’s multiple comparison test with groups compared to PBS. Replicates are biological, and data are shown as mean ± s.e.m. Panel a created with BioRender.com.
a, Scheme depicting the concept of an albumin-hitchhiking nanobody–STING agonist conjugate for cancer immunotherapy. Anti-albumin nanobodies conjugated to STING agonists bind to circulating albumin in situ, resulting in improved pharmacokinetics and increased biodistribution to tumour sites that stimulates antitumour innate and adaptive immune responses. b, Computational model of the anti-albumin nanobody (nAlb) binding at domain IIB of HSA. c, ITC traces (top) and binding isotherms (bottom) of nAlb binding to human and mouse serum albumin at pH 7.5 with calculated dissociation constant (Kd). d, Reaction scheme for generating molecularly homogeneous nAlb conjugates through site-selective enzymatic ligation of an amine-PEG3-azide followed by conjugation of agonist or dye cargo through strain-promoted azide-alkyne cycloaddition (SPAAC). e, Structure of diABZI STING agonist conjugated to a DBCO-PEG11 handle for ligation to azide-functionalized nanobodies via SPAAC. f,g, ESI–MS (f) and SDS–PAGE (g) showing nanobody conjugate purity and molecular weight (see Source Data for uncropped gel in ref. 90). h,i, Dose–response curves in A549-Dual (n = 3) (h) and THP1-Dual type I interferon reporter cell lines (n = 3) (i) with estimated EC50 values indicated in the legends; RLU, relative light unit. j, qPCR analysis of gene expression in mouse BMDMs treated in vitro with 0.25 µM of free diABZI or nAlb–diABZI conjugate (n = 3). P values determined by one-way ANOVA with Dunnett’s multiple comparison test with groups compared to PBS. Replicates are biological, and data are shown as mean ± s.e.m. Panel a created with BioRender.com.

Congratulations to Blaise Kimmel! Blaise’s article, “Potentiating cancer immunotherapies with modular albumin-hitchhiking nanobody-STING agonist conjugates,” published in Nature Biomedical Engineering has been selected as a VINSE spotlight publication. The work was completed during his postdoctoral fellowship at Vanderbilt University with Dr. John Wilson, where he developed modular immunoengineering strategies to enhance cancer immunotherapy. Blaise is now the Umit S. Ozkan Assistant Professor at The Ohio State University.

In this study, Blaise and collaborators report a modular nanobody-based platform that enhances the delivery and potency of STING agonists by extending circulation time and increasing tumor accumulation. The approach enables simultaneous immune activation and immune checkpoint blockade, resulting in strong antitumor immune responses and long-lasting immune memory in preclinical models. The work includes contributions from Lauren Hubert, a Vanderbilt VINSE Research Experiences for Undergraduates (REU) participant and co-author on the publication.

This research highlights the impact of interdisciplinary immunoengineering at Vanderbilt and its potential for advancing next-generation cancer therapies.

Authors: Blaise R. Kimmel, Karan Arora, Neil C. Chada, Vijaya Bharti, Alexander J. Kwiatkowski, Jonah E. Finkelstein, Ann Hanna, Emily N. Arner, Taylor L. Sheehy, Lucinda E. Pastora, Jinming Yang, Hayden M. Pagendarm, Payton T. Stone, Ebony Hargrove-Wiley, Brandie C. Taylor, Lauren A. Hubert, Barbara M. Fingleton, Katherine N. Gibson-Corley, Jody C. May, John A. McLean, Jeffrey C. Rathmell, Ann Richmond, W. Kimryn Rathmell, Justin M. Balko, John T. Wilson

Abstract. The enhancement of antitumour immunity via agonists of the stimulator of interferon genes (STING) pathway is limited by pharmacological barriers. Here we show that the covalent conjugation of a STING agonist to anti-albumin nanobodies via site-selective bioconjugation chemistries prolongs the circulation of the agonist in the blood and increases its accumulation in tumour tissue, stimulating innate immune programmes that increased the infiltration of activated natural killer cells and T cells, which potently inhibited the growth of mouse tumours. The technology is modular, as demonstrated by the recombinant integration of a second nanobody domain targeting programmed death-ligand 1 (PD-L1), which further increased the accumulation of the agonist in tumours while blocking immunosuppressive PD-1/PD-L1 interactions. The bivalent nanobody–STING agonist conjugate stimulated robust antigen-specific T-cell responses and long-lasting immunological memory and conferred enhanced therapeutic efficacy. It was also effective as a neoadjuvant treatment to adoptive T-cell therapy. As a modular approach, hitchhiking STING agonists on serum albumin may serve as a broadly applicable strategy for augmenting the potency of systemically administered cancer immunotherapies.

Volume 9 | October 2025 | 1719–1739
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——-> Read Ohio State News Press Release

 

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