Engineering strategies and decision frameworks for virus-like particle-based vaccines against infectious diseases

Virus-like particles (VLPs) have emerged as a versatile and clinically validated platform for developing safe, effective vaccines against infectious diseases. However, the expanding toolkit of VLP engineering strategies-spanning genetic fusion, modular conjugation, and nucleic acid encapsulation-creates a critical need for a rational selection framework to match technological strengths with specific vaccine objectives. This review addresses this gap by constructing a comparative decision-making framework centered on four core engineering dimensions: cargo flexibility, loading specificity, functional efficiency, and manufacturability. We systematically juxtapose two principal technology streams: (1) the display of protein antigens (through genetic, chemical, and bio-conjugation) and (2) the encapsulation of nucleic acid cargo (via physical, electrostatic, and programmable packaging mechanisms), evaluating each within this unified framework. This technological dissection is directly linked to the development landscape of VLP-based vaccines against major pathogens-including HBV, HPV, malaria, influenza, and SARS-CoV-2-illustrating how strategic choices at the engineering level fundamentally underpin immunogenic potency and translational success. By sequentially considering immunological objectives, antigen compatibility, surface display modality, interior cargo integration, and manufacturing constraints, this framework facilitates rational, stepwise VLP vaccine design. Looking forward, we discuss emerging trends toward modular and computationally guided platforms for antigen placement and scaffold design. By integrating a structured technology assessment with translational insights, this review aims to provide a practical roadmap for the rational design and accelerated development of next-generation, broadly protective VLP-based vaccines.