Chemically Programmed Albumin–Enzyme Conjugates to Induce Microenvironment-Responsive Metabolic Disruption
5 affiliations
- 1Max Planck Institute for Polymer Research, Ackermannweg 10, Mainz, Germany, 55128
- 2Ulm University, Albert-Einstein-Allee 11, Ulm, Germany, 89081
- 3Institute of Immunology of the Research Center for Immunotherapy (FZI
- 4University Medical Center, Johannes Gutenberg University Mainz
- 5German Cancer Consortium (DKTK
Abstract
Glucose oxidase (GOx)-mediated glucose depletion is an attractive intervention strategy that can address the abnormal tumor metabolism characterized by elevated glycolysis. But its efficacy is limited by inefficient cellular delivery and hypoxia-induced stabilization of HIF-1α, which is associated with adaptive metabolic responses. Here, we report a chemically programmed albumin–GOx conjugate that couples microenvironment-responsive uptake with reductive release of acriflavine (ACF), a small molecule reported to interfere with HIF-1 signaling. Human serum albumin was used as the core carrier platform and engineered to include (1) dimethylmaleic anhydride groups to sense tumor-relevant acidic conditions and induce charge reversal for concomitant cellular delivery of both GOx and ACF payloads and (2) self-immolative disulfide linkage to release ACF under reductive conditions. The resulting GOx–albumin–ACF conjugate preserved GOx-mediated glucose oxidation and attenuated HIF-1α accumulation. Consequently, stronger metabolic disruption including suppressed lactate production and reduced adenosine triphosphate (ATP) levels was observed, together with enhanced cell death in two-dimensional cultures and three-dimensional tumor spheroids. By integrating chemical activation with modulation of the GOx-associated HIF-1α response, this work establishes a biomacromolecular design strategy for a protein-based, microenvironment-responsive therapeutic system that senses, responds, and acts within the tumor microenvironment to achieve enhanced metabolic disruption and cytotoxicity
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BibTeX
@misc{hu2026chemically,
title = {{Chemically Programmed Albumin–Enzyme Conjugates to Induce Microenvironment-Responsive Metabolic Disruption}},
author = {Lifan Hu and Yulian Cheng and Jiyao Yu and Maria J. S. A. Silva and Lin Jian and Toszka Bohn and Kaloian Koynov and Seah Ling Kuan and Tanja Weil},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15011191/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15011191/v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Chemically Programmed Albumin–Enzyme Conjugates to Induce Microenvironment-Responsive Metabolic Disruption
AU - Lifan Hu
AU - Yulian Cheng
AU - Jiyao Yu
AU - Maria J. S. A. Silva
AU - Lin Jian
AU - Toszka Bohn
AU - Kaloian Koynov
AU - Seah Ling Kuan
AU - Tanja Weil
PY - 2026
DA - 2026/10/28
PB - ChemRxiv
DO - 10.26434/chemrxiv.15011191/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15011191/v1
AB - Glucose oxidase (GOx)-mediated glucose depletion is an attractive intervention strategy that can address the abnormal tumor metabolism characterized by elevated glycolysis. But its efficacy is limited by inefficient cellular delivery and hypoxia-induced stabilization of HIF-1α, which is associated with adaptive metabolic responses. Here, we report a chemically programmed albumin–GOx conjugate that couples microenvironment-responsive uptake with reductive release of acriflavine (ACF), a small molecule reported to interfere with HIF-1 signaling. Human serum albumin was used as the core carrier platform and engineered to include (1) dimethylmaleic anhydride groups to sense tumor-relevant acidic conditions and induce charge reversal for concomitant cellular delivery of both GOx and ACF payloads and (2) self-immolative disulfide linkage to release ACF under reductive conditions. The resulting GOx–albumin–ACF conjugate preserved GOx-mediated glucose oxidation and attenuated HIF-1α accumulation. Consequently, stronger metabolic disruption including suppressed lactate production and reduced adenosine triphosphate (ATP) levels was observed, together with enhanced cell death in two-dimensional cultures and three-dimensional tumor spheroids. By integrating chemical activation with modulation of the GOx-associated HIF-1α response, this work establishes a biomacromolecular design strategy for a protein-based, microenvironment-responsive therapeutic system that senses, responds, and acts within the tumor microenvironment to achieve enhanced metabolic disruption and cytotoxicity
ER -