Chirality Targets Lysosomes

Reflecting work in the Li and Chen Labs

Published here September 24, 2026

Sensitizing Self-Assembly of Peptide-Drug Conjugates via Chiral Engineering to Evoke Tumor Ferroptosis

Jinmin Ye, Yangkai Zhou, Wenjiao Fu, Rongrong Qiao, Xingru Liu, Shijian Liang, Huipeng Ma, Zhi Huang, Jiayang Li, and Chunying Chen

J. Am. Chem. Soc. 2026, 148, 32497–32508. https://doi.org/10.1021/jacs.6c09475

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Responsive supramolecular assemblies that sense pH, redox state, or enzymatic activity have emerged as a compelling platform for targeted cancer therapy, yet programming them to act at a precise subcellular address remains a persistent challenge. Most strategies require adding chemically labile linkages or responsive motifs that demand extra synthetic steps and can compromise the structural integrity of the conjugate. A subtler lever, the stereochemistry of the backbone itself, has attracted interest, but its consequences for biological fate inside living cells have remained largely unexplored. If chirality could redirect where a peptide-drug conjugate assembles, from the cell surface to the lysosomal lumen, an entirely new axis of spatiotemporal control would open up.

Researchers in the Li Lab at the National Center for Nanoscience and Technology of China, published in J. Am. Chem. Soc., show that alternating D/L residues in a naphthalene-capped Phe-Phe-Lys tripeptide conjugated to a carbonic anhydrase IX, CAIX, inhibitor confer sharply heightened pH sensitivity on self-assembly without altering the molecular backbone. The key observation is a chiral-sequence-specific pKa shift: the heterochiral isomer DLD-ABS, carrying alternating D/L chirality, undergoes a more than 40-fold drop in critical micellization concentration as pH falls from 7.5 to 5.5, transitioning from nanospheres to amyloid-like nanofibers, while the homochiral DDD-ABS remains fibrous across the same range. The authors trace this to a protonation-induced conformational rearrangement that is kinetically gated by the heterochiral backbone geometry. In CAIX-overexpressing triple-negative breast cancer cells under hypoxia, CAIX-mediated endocytosis carries DLD-ABS into lysosomes as nanospheres; the acidic lysosomal environment then triggers fiber formation in situ. The resulting intraluminal fibers rupture the lysosomal membrane, releasing Fe2+ into the cytosol and amplifying the Fenton reaction, while concurrent CAIX inhibition further perturbs redox homeostasis, driving cells toward ferroptosis.

The findings establish chirality as a low-footprint design parameter for controlling the subcellular address of self-assembling conjugates and offer a mechanistic explanation for heterochirality-dependent biological effects. For the peptide community, the work points toward therapeutic systems that exploit the tumor lysosomal microenvironment as a trigger rather than a barrier, with in vivo antitumor outcomes in breast tumor xenografts that underscore the translational reach of the approach.

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Additional Authors

Author

Yangkai Zhou is a Ph.D. student at National Center for Nanoscience and Technology under the supervision of Prof. Chunying Chen. He received his B.S. degree in 2022 from the College of Nanoscience and Technology at Soochow University. His research focuses on peptide phase transitions and chiral biomedical effects.

Author

Jiayang Li received her B.S. degree in Chemistry in 2007, from Hong Kong University of Science and Technology and earned her Ph.D. in Chemistry in 2013 from Brandeis University, USA. She works as Professor at the National Center for Nanoscience and Technology of China. Her research interests lie in developing novel nanomedicines with high efficiency and low toxicity for tumor theranostic.

Author

Prof. Chunying Chen received her Bachelor’s degree in Chemistry in 1991, and obtained her Ph.D. in Biomedical Engineering from Huazhong University of Science and Technology of China in 1996. She worked as a postdoctoral research fellow at the Key Laboratory of Nuclear Analytical Techniques, Institute of High Energy Physics of Chinese Academy of Sciences, 1996–1998, and at the Medical Nobel Institute for Biochemistry of Karolinska Institute, Sweden, 2001–2002. She has been a professor and a group leader at National Center for Nanoscience and Technology since 2006. She was elected as a Academician of Chinese Academy of Sciences in 2023 and Fellow of the World Academy of Sciences, TWAS, in 2024. She is also a fellow of the American Institute for Medical and Biological Engineering, starting in 2021, and the Royal Society of Chemistry in 2016.

Chirality Targets Lysosomes

Author Spotlight

Author

Jinmin Ye is a Postdoctoral Researcher at the First Affiliated Hospital of Xiamen University, China. She earned her M.Sc. from Jinan University in 2022 through a joint graduate training program with the National Center for Nanoscience and Technology. She earned her Ph.D. in Medicine from Xiamen University in 2026. Under Prof. Chunying Chen’s supervision Her research interests focus on self-assembling nanomedicines, peptide-drug conjugates, and the regulation of ferroptosis and immune cell function for the treatment of inflammation-associated diseases.