Hyaluronic acid-based nanoparticles in cancer diagnosis and therapy: Molecular weight matters
- 1Department of Nuclear Medicine, China-Japan Union Hospital of Jilin University, Changchun, 130033, China
- 2Department of Surgery, Emory University School of Medicine, Atlanta, GA, 30322, United States
Abstract
Hyaluronic acid (HA)-based nanomaterials have emerged as promising platforms for cancer therapy owing to their excellent biocompatibility, biodegradability, and intrinsic tumor-targeting capability. However, the intrinsic biological functions of HAs are profoundly affected by molecular weight (MW), a factor that remains underappreciated in current nanocarrier design. Accumulating evidence indicates that HA exhibits distinct MW-dependent functions that high MW HA (HMW-HA) primarily supports tissue homeostasis and anti-inflammatory signaling, whereas low MW (LMW-HA) and oligomeric HA (oligo-HA) act as bioactive mediators that promote inflammation, angiogenesis, and tumor progression. Currently, most HA-based drug delivery strategies continue to treat HA mainly as a passive carrier, largely neglecting its MW-dependent biological activity and its impact on therapeutic outcomes. To address this gap, this review proposes a MW-structure-function framework for the rational design of HA-based nanomedicines. We first summarize the MW-dependent biological behaviors of HA across physiological and pathological contexts, with a particular focus on its role in the tumor microenvironment (TME). We then examine how MW regulates nanoparticle self-assembly, physicochemical properties, and interactions with biological systems, thereby influencing biodistribution, cellular uptake, and therapeutic efficacy. Building on these insights, we highlight recent advances in MW-optimized HA nanoplatforms for tumor imaging and multimodal therapies, including chemotherapy, phototherapy, and immunotherapy. Lastly, we discuss the key challenges and future directions, emphasizing the need to integrate the intrinsic biological activity of HA into nanocarrier engineering. This review aims to redefine HA-based nanoparticles from passive delivery vehicles into programmable bioactive nanoplatforms, providing a conceptual foundation for next-generation cancer nanomedicine.
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BibTeX
@article{zhang2026hyaluronic,
title = {{Hyaluronic acid-based nanoparticles in cancer diagnosis and therapy: Molecular weight matters}},
author = {Zhining Zhang and Mengshi Ma and Yunpeng Dai and Minglong Chen and Lei Zhu and Shi Gao},
journal = {Materials Today Bio},
year = {2026},
month = oct,
doi = {10.1016/j.mtbio.2026.103773},
url = {https://doi.org/10.1016/j.mtbio.2026.103773},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Hyaluronic acid-based nanoparticles in cancer diagnosis and therapy: Molecular weight matters
AU - Zhining Zhang
AU - Mengshi Ma
AU - Yunpeng Dai
AU - Minglong Chen
AU - Lei Zhu
AU - Shi Gao
PY - 2026
DA - 2026/10/23
JO - Materials Today Bio
DO - 10.1016/j.mtbio.2026.103773
UR - https://doi.org/10.1016/j.mtbio.2026.103773
AB - Hyaluronic acid (HA)-based nanomaterials have emerged as promising platforms for cancer therapy owing to their excellent biocompatibility, biodegradability, and intrinsic tumor-targeting capability. However, the intrinsic biological functions of HAs are profoundly affected by molecular weight (MW), a factor that remains underappreciated in current nanocarrier design. Accumulating evidence indicates that HA exhibits distinct MW-dependent functions that high MW HA (HMW-HA) primarily supports tissue homeostasis and anti-inflammatory signaling, whereas low MW (LMW-HA) and oligomeric HA (oligo-HA) act as bioactive mediators that promote inflammation, angiogenesis, and tumor progression. Currently, most HA-based drug delivery strategies continue to treat HA mainly as a passive carrier, largely neglecting its MW-dependent biological activity and its impact on therapeutic outcomes. To address this gap, this review proposes a MW-structure-function framework for the rational design of HA-based nanomedicines. We first summarize the MW-dependent biological behaviors of HA across physiological and pathological contexts, with a particular focus on its role in the tumor microenvironment (TME). We then examine how MW regulates nanoparticle self-assembly, physicochemical properties, and interactions with biological systems, thereby influencing biodistribution, cellular uptake, and therapeutic efficacy. Building on these insights, we highlight recent advances in MW-optimized HA nanoplatforms for tumor imaging and multimodal therapies, including chemotherapy, phototherapy, and immunotherapy. Lastly, we discuss the key challenges and future directions, emphasizing the need to integrate the intrinsic biological activity of HA into nanocarrier engineering. This review aims to redefine HA-based nanoparticles from passive delivery vehicles into programmable bioactive nanoplatforms, providing a conceptual foundation for next-generation cancer nanomedicine.
SN - 2590-0064
ER -