Programmable Peptides Activated Macropinocytosis for Direct Cytosolic Delivery

Area of Science:

• Biotechnology
• Drug Delivery
• Nanomedicine

Background:

• Bioactive macromolecules hold therapeutic potential but face challenges in cytosolic delivery.
• Intracellular barriers and poor endosomal escape limit the efficacy of peptide-based drugs.

Purpose of the Study:

• To develop programmable self-assembling peptide vectors for efficient cytosolic drug delivery.
• To overcome intracellular barriers and enhance the uptake of peptide-based therapeutics.

Main Methods:

• Utilized programmable self-assembling peptide vectors to activate human epidermal growth factor receptor-2 (HER2) signaling.
• Induced receptor-activated macropinocytosis for enhanced cargo internalization into tumor cells.
• Investigated assembly dynamics within shrinking macropinosomes for nanostructure formation and cargo retention.

Main Results:

• Achieved efficient uptake of peptide-based cargo in tumor cells via macropinocytosis.
• Demonstrated a 2.5-fold improvement in Gadolinium (Gd) delivery efficiency in tumor tissue compared to active targeting.
• Maintained high drug activity (twofold decrease in IC50) and effective tumor cell growth inhibition.

Conclusions:

• Programmable self-assembling peptide vectors facilitate efficient intracellular drug delivery through macropinocytosis.
• This platform enhances cargo accumulation and retention in the cytoplasm, improving therapeutic efficacy.
• Represents a versatile platform for delivering diverse bioactive drugs, including peptides and biologics.