Hyperbranched Polylysine-Based Lipopolyplexes Enable Efficient mRNA Delivery With Long-Term Storage Stability

  • Adv Healthc Mater. 2026 Sep;15(34):e71571. doi: 10.1002/adhm.71571.
Huidi Meng  1  2 ,  Bingjie Fu  1  2 ,  Min Liang  2 ,  Qiaoxuan Wang  3  4 ,  Xingpu Liu  1  2 ,  Man Li  1  2 ,  Qiaoju Hu  2 ,  Yiyuan Duan  2 ,  Changyou Gao  1  2  3  4  5
Affiliations
  • 1. College of Engineers, Zhejiang University, Hangzhou, China.
  • 2. Zhejiang Engineering Research Center for Interface Technology of Medical Polymers and Devices, Shaoxing Key Laboratory of Healthcare Materials and Application Technology, and Center for Healthcare Materials, Shaoxing Institute, Zhejiang University, Shaoxing, China.
  • 3. Zhejiang Key Laboratory of Advanced Organic Materials and Technologies, MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China.
  • 4. Dr. Li Dak Sum Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, China.
  • 5. The State Key Laboratory of Transvascular Implantation Devices, Zhejiang University, Hangzhou, China.
PMID: 42590857 DOI: 10.1002/adhm.71571
Abstract

Clinical translation of messenger RNA (mRNA) therapeutics is often hampered by the poor storage stability of lipid-based delivery vectors. Many lipopolyplex (LPP) delivery systems struggle to achieve efficient nucleic acid release through the membrane fusion pathway. Herein, we developed a novel ternary lipopolyplex (LPP) platform of lipid/HBPL/mRNA LPPs by incorporating hyperbranched poly-L-lysine (HBPL) as a functional polymeric core. The highly branched architecture of HBPL enabled a unique balance between high mRNA encapsulation efficiency, efficient intracellular release, and exceptional colloidal stability, thereby overcoming a key limitation of conventional Lipid Nanoparticles. This platform primarily promoted cellular uptake through a membrane fusion mechanism in vitro, thereby achieving highly efficient cytoplasmic delivery, while the HBPL core enabled superior mRNA release compared to its linear ε-Polylysine (ε-PLL, hereafter referred to as PLL)-based counterpart. These attributes collectively yielded high transfection efficiency across multiple cell lines, significantly enhanced dendritic cell (DC) maturation, and superior biocompatibility over a commercial transfection reagent. Efficient mRNA delivery to the Lungs and spleen was also confirmed in vivo, with protein expression sustained even after 1 month of storage. By successfully integrating long-term stability with high delivery efficiency, this HBPL-based LPP platform represents a highly promising candidate for advancing mRNA therapeutics and vaccines.

Keywords
hyperbranched polylysine; lipopolyplexes; mRNA delivery; membrane fusion; stability.
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