Nucleus-targeted protein delivery via lysine dendron conjugation

Area of Science:

• Bioconjugation Chemistry
• Drug Delivery Systems
• Molecular Therapeutics

Background:

• Targeted delivery of therapeutic proteins to the cell nucleus remains a significant challenge in drug development.
• Existing protein delivery methods often require complex surface modifications and lack efficiency.
• Overcoming these limitations is crucial for advancing protein-based therapeutics.

Purpose of the Study:

• To introduce a novel lysine dendron (LD)-mediated strategy for efficient nucleus-targeted protein delivery.
• To demonstrate the efficacy of multivalent LD-protein architectures in enhancing cellular uptake and nuclear accumulation.
• To evaluate the therapeutic potential of LD-modified proteins, specifically RNase A, for cancer treatment.

Main Methods:

• Utilizing click chemistry for the conjugation of lysine dendrons (LDs) to proteins.
• Developing multivalent LD-protein architectures for enhanced biological interactions.
• Assessing cellular uptake and nuclear localization of LD-modified proteins in vitro.
• Evaluating the antitumor efficacy of LD-modified RNase A in vitro and in vivo.

Main Results:

• Lysine dendron conjugation significantly enhanced cellular uptake and nuclear accumulation of proteins.
• LD-modified RNase A exhibited superior nuclear delivery compared to unmodified RNase A.
• Significant antitumor efficacy was observed for LD-modified RNase A in both in vitro and in vivo models.
• The bioreversible nature of the LD-protein conjugation was confirmed.

Conclusions:

• Lysine dendron-mediated protein conjugation is an effective strategy for nucleus-targeted delivery.
• This approach offers a versatile and efficient platform for developing next-generation protein therapeutics.
• The developed bioreversible strategy overcomes limitations of traditional protein delivery systems.