Rod-Shaped Active Drug Particles Enable Efficient and Safe Gene Delivery.

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Gene Therapy

Background:

• Efficient intracellular delivery of microRNAs (miRNAs) is crucial for disease therapy but hindered by conventional nonviral vectors' lysosomal entrapment and poor cytosolic escape (<2%).
• Existing vectors face limitations in gene escape from lysosomes, impacting therapeutic efficacy.

Purpose of the Study:

• To develop and evaluate novel rod-shaped active pure drug nanoparticles (PNPs) for efficient microRNA (miRNA) delivery.
• To assess the intracellular delivery efficiency, therapeutic efficacy, and safety of PNPs carrying lethal-7a (let-7a) for disease treatment.

Main Methods:

• Synthesis of rod-shaped active pure drug nanoparticles (PNPs) with high drug-loading capacity (≈300%).
• Complexation of PNPs with lethal-7a (let-7a) to form complexes (CNPs) for intracellular delivery.
• Evaluation of cellular uptake, lysosomal escape, KRAS protein expression reduction, pharmacokinetic profiles, tumor accumulation, and in vivo antitumor efficacy and safety.

Main Results:

• Developed PNPs/let-7a complexes (CNPs) efficiently delivered let-7a into the cytosol, bypassing the lysosomal pathway.
• Achieved a 50% reduction in target protein (KRAS) expression.
• CNPs demonstrated a threefold increase in blood circulation half-life (t1/2) and 1.5-2-fold enhanced tumor accumulation.
• Significant improvements in antitumor efficacy were observed with no damage to normal organs.

Conclusions:

• Rod-shaped active PNPs provide an efficient and safe platform for miRNA delivery, enabling synergistic disease treatment.
• This nanoplatform shows potential for effective in vitro and in vivo delivery of proteins and peptides.