Rationally engineered cationic ferritin nanoparticles overcome pre-existing immunity to adenoviral vectors

Area of Science:

• Nanotechnology
• Vaccinology
• Molecular Biology

Background:

• Viral vectors and protein nanoparticles are key vaccine delivery platforms.
• Pre-existing immunity to viral vectors limits vaccine effectiveness.
• Synergistic strategies to overcome biological barriers are underexplored.

Purpose of the Study:

• To engineer a novel protein nanoparticle to overcome pre-existing immunity against viral vectors.
• To create a supramolecular complex of cationic ferritin and adenovirus.
• To evaluate the efficacy of this complex for vaccine delivery.

Main Methods:

• Rational engineering of cationic human ferritin (hF) nanoparticles (+)hF via structure-guided mutations.
• Electrostatic assembly of (+)hF with adenovirus serotype 5 (Ad5) into nanocomplexes.
• In vitro and in vivo assessment of transgene expression, neutralization sensitivity, and immunogenicity in murine models.

Main Results:

• (+)hF nanoparticles formed stable nanocomplexes with Ad5.
• These nanocomplexes enhanced transgene expression and reduced sensitivity to anti-Ad5 neutralization.
• Intranasal immunization with (+)hF-Ad5 complexes elicited significantly higher antigen-specific IgG and neutralizing antibody titers in mice with pre-existing immunity.
• (+)hF's endogenous origin ensured high biocompatibility without inducing anti-carrier antibodies.

Conclusions:

• Engineered cationic ferritin nanoparticles provide a versatile platform for synergistic delivery with viral vectors.
• This strategy effectively circumvents pre-existing immunity against viral vectors.
• The (+)hF-Ad5 nanocomplexes represent a promising approach for enhanced vaccine and gene delivery applications.