TRAIL & EGFR affibody dual-display on a protein nanoparticle synergistically suppresses tumor growth

Area of Science:

• Biotechnology and Nanomedicine
• Cancer Therapeutics
• Molecular Biology

Background:

• TNF-related apoptosis-inducing ligand (TRAIL) shows promise for cancer treatment due to selective cancer cell apoptosis induction.
• TRAIL's therapeutic efficacy is limited by poor pharmacokinetics and resistance mediated by the EGF/EGFR survival pathway.
• EGFR-overexpressing cancers present a significant therapeutic challenge, often requiring combination strategies.

Purpose of the Study:

• To engineer a novel nanoplatform for dual-target cancer therapy.
• To overcome TRAIL resistance and target EGFR-positive cancers.
• To evaluate the efficacy and safety of the developed therapeutic in vitro and in vivo.

Main Methods:

• Utilized an Aquifex aeolicus lumazine synthase (AaLS) protein cage as a nanoplatform.
• Employed a SpyTag/SpyCatcher system for polyvalent display of TRAIL and EGFR affibody (EGFRAfb) molecules.
• Assessed cytotoxicity, apoptosis induction, signaling pathway disruption, tumor targeting, and in vivo efficacy in A431 cancer models.

Main Results:

• The dual-ligand nanoparticle (AaLS/TRAIL/EGFRAfb) demonstrated significantly enhanced cytotoxicity against TRAIL-resistant, EGFR-overexpressing A431 cancer cells.
• The nanotherapy effectively disrupted EGF-mediated EGFR survival signaling and synergistically activated extrinsic and intrinsic apoptotic pathways.
• AaLS/TRAIL/EGFRAfb showed selective targeting of cancer cells in vitro, reached tumor sites in vivo, and significantly suppressed tumor growth with minimal side effects.

Conclusions:

• AaLS/TRAIL/EGFRAfb represents a potent protein-based therapeutic strategy for EGFR-positive cancers.
• This dual-targeting approach effectively overcomes resistance mechanisms associated with monotherapy.
• The developed nanoplatform holds significant potential for treating challenging cancers that are poorly managed by single-agent therapies.