2. Academic Validation
  3. A general nanoplatform for nucleotide drug delivery: From molecular binding to antiviral therapy

A general nanoplatform for nucleotide drug delivery: From molecular binding to antiviral therapy

  • J Control Release. 2025 Sep 18:387:114245. doi: 10.1016/j.jconrel.2025.114245.
Zheng Zhou 1,  Fan Zhang 2,  Xiang Li 3,  Yina Zhang 4,  Xiahong Xie 5,  Qifan Liu 6,  Pingan Xia 7,  Xinping Wang 8,  Mingzhou Ye 9
Affiliations

Affiliations

  • 1 School of Nano-Technology and Nano-Bionics, University of Science and Technology of China, Hefei 230026, China; Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, Jiangsu Province, China. Electronic address: zzhou2022@sinano.ac.cn.
  • 2 Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, Jiangsu Province, China; State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130000, China. Electronic address: fzhang2023@sinano.ac.cn.
  • 3 School of Nano-Technology and Nano-Bionics, University of Science and Technology of China, Hefei 230026, China; Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, Jiangsu Province, China. Electronic address: xiangli2023@sinano.ac.cn.
  • 4 College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan, China. Electronic address: Zynn521@163.com.
  • 5 Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, Jiangsu Province, China. Electronic address: xhxie2022@sinano.ac.cn.
  • 6 Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, Jiangsu Province, China. Electronic address: qfliu2023@sinano.ac.cn.
  • 7 College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan, China. Electronic address: Xpa88@163.com.
  • 8 State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun 130000, China. Electronic address: wangxp88@hotmail.com.
  • 9 School of Nano-Technology and Nano-Bionics, University of Science and Technology of China, Hefei 230026, China; Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, Jiangsu Province, China. Electronic address: mzye2021@sinano.ac.cn.
PMID: 40975176 DOI: 10.1016/j.jconrel.2025.114245
Abstract

Nucleoside-based agents represent an important class of therapeutics for viral infections and malignancies. Their pharmacologically active forms, nucleoside triphosphates (TPs), exhibit high polarity and negative charge severely limiting cellular uptake and intracellular utilization. While prodrug strategies used in clinical practice often exhibit limited activation and efficacy, nanocarrier-based TP delivery offers a promising alternative; however, efficient encapsulation of these highly hydrophilic small molecules remains a great challenge. To address this, we developed a rationally designed polymeric carrier PGB, featuring alternating phenylboronic acid and guanidinium groups that bind to conserved nucleotide motifs through multivalent interactions. This design achieves an association constant up to 5.19 × 108 with ATP at pH 7.4, facilitates efficient cytosolic delivery, and enhances Antiviral efficacy across multiple viral Infection models. In an H1N1-infected mouse model, the nanoparticle formulation demonstrated a markedly improved pharmacokinetic profile compared to the Antiviral drug Molnupiravir, effectively suppressed viral replication, reduced pulmonary inflammatory cell infiltration, and preserved lung structure and function. Our study successfully achieved the efficient loading and intracellular delivery of hydrophilic molecules, providing a versatile and broadly applicable platform for nucleotide drug delivery.

Keywords

Antiviral nanoparticles; H1N1 influenza; Nanomedicine; Nucleoside drugs; PBAE polymer.

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