A localizing nanocarrier formulation enables multi-target immune responses to multivalent replicating RNA with...

Area of Science:

• Vaccinology
• Nanotechnology
• Immunology

Background:

• Self-amplifying RNA (repRNA) vaccines show promise but trigger potent innate immune responses in vivo, limiting efficacy and causing side effects.
• Current repRNA vaccine delivery methods can lead to reduced transgene expression and dose-limiting reactogenicity, as observed in clinical trials.

Purpose of the Study:

• To investigate a novel nanocarrier formulation (LION) for safe and effective delivery of multivalent repRNA vaccines.
• To compare the immunogenicity and safety profile of LION-delivered repRNA with traditional lipid nanoparticle (LNP) delivery.

Main Methods:

• Development and utilization of a localizing cationic nanocarrier formulation (LION) for multivalent repRNA delivery.
• Intramuscular administration of multivalent repRNA via LION and LNPs in a mouse model.
• Assessment of biodistribution, innate and adaptive immune responses, and systemic inflammatory markers.

Main Results:

• LION facilitated safe intramuscular delivery of higher doses of multivalent repRNA, showing localized biodistribution and upregulated local innate immunity.
• LION-delivered repRNA induced robust antigen-specific adaptive immune responses without systemic inflammation or significant body weight loss.
• In contrast, LNP delivery resulted in generalized biodistribution, systemic inflammation, body weight loss, and failed to induce neutralizing antibodies in a multivalent setting.

Conclusions:

• The LION nanocarrier platform enables safe and effective multivalent repRNA vaccination by controlling biodistribution and localizing immune responses.
• LION represents a distinct and advantageous delivery mechanism compared to LNPs for repRNA vaccines, particularly for multivalent applications.