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Enhanced Targeted Drug Delivery System to Control Avidity and Drug Encapsulation Using E2 Nanocages and
Dohee Ahn1, Sun Hee Park2,3, Yeong Geun Lee1,3
1Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon 16419, Republic of Korea.
ACS Biomaterials Science & Engineering
|April 10, 2025
Summary
Engineered protein nanocages deliver potent anticancer drugs by precisely targeting HER2-positive cancer cells. This advanced drug delivery system enhances binding avidity and exhibits strong cytotoxicity, paving the way for next-generation cancer therapies.
Area of Science:
- Biotechnology
- Nanotechnology
- Oncology
Background:
- Antibody-drug conjugates face limitations in carrying hydrophobic payloads.
- Protein nanocages offer advantages for targeted drug delivery, including precise assembly and biocompatibility.
Purpose of the Study:
- To develop engineered E2 protein nanocages for targeted delivery of hydrophobic anticancer drugs.
- To control the display valency of anti-HER2 single-chain variable fragments (scFv) on nanocages using the SpyTag/SpyCatcher system.
- To evaluate the impact of scFv valency on HER2 binding avidity and the cytotoxicity of drug-loaded nanocages.
Main Methods:
- Engineered E2 nanocages were functionalized with anti-HER2 scFv using SpyTag/SpyCatcher ligation to control valency.
- Cysteine residues were introduced for conjugation with monomethyl auristatin E (MMAE) via maleimide chemistry.
- Cytotoxicity was assessed in HER2-positive (SKBR3, BT-474) and HER2-negative (MDA-MB-231) cell lines.
Main Results:
- Increased anti-HER2 scFv valency enhanced HER2 binding affinity through avidity effects.
- Efficient loading of MMAE onto E2 nanocages was achieved.
- MMAE-conjugated nanocages demonstrated potent subnanomolar cytotoxicity against HER2-positive cells while sparing HER2-negative cells.
Conclusions:
- ScFv valency is critical for enhancing HER2 targeting and binding avidity.
- E2 protein nanocages represent a promising platform for specific and potent targeted cancer therapy.
- The modular design and pH-sensitive dissociation of these nanocages support future precision medicine strategies.
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