Membrane Fusion Mediated Targeted Cytosolic Drug Delivery Through scFv Engineered Sendai Viral Envelopes

Area of Science:

• Biotechnology
• Drug Delivery
• Oncology

Background:

• Antibody-mediated drug delivery often leads to endosomal entrapment, limiting therapeutic efficacy.
• Cytoplasmic delivery is challenging but offers advantages like reduced payload degradation and immunogenicity.
• Sendai viral envelopes facilitate cytoplasmic delivery via F-protein mediated membrane fusion.

Purpose of the Study:

• To engineer an immuno-virosome for targeted cytoplasmic drug delivery.
• To utilize a recombinant antibody fragment targeting Placental Alkaline Phosphatase (PAP) for specific cancer cell recognition.
• To leverage Sendai virus fusion proteins for efficient payload release into the cytoplasm.

Main Methods:

• Generated a fusion protein combining an anti-PAP scFv with the Sendai virus F protein's transmembrane and cytoplasmic domains (F(TMC)).
• Reconstituted virosomes incorporating the fusion protein and native F-protein.
• Tested the immuno-virosomes for specific binding and drug delivery to PAP-expressing cells.

Main Results:

• Virosomes specifically bound to and delivered drugs into PAP-expressing cells.
• Achieved approximately 75% cytoplasmic drug delivery.
• The immuno-virosomes, lacking the toxic HN protein, demonstrated targeted delivery and cytoplasmic access.

Conclusions:

• Developed a novel immuno-virosome capable of specific antibody-mediated targeting and efficient cytoplasmic drug delivery.
• The approach overcomes endosomal entrapment, offering potential for improved cancer therapy.
• The ubiquitous expression of PAP in various cancers highlights the broad applicability of this delivery system.