Drawing on insights from mRNA vaccine development, this talk highlights advances in LNP design and their expanding role in mRNA therapeutics for cancer immunotherapy, with a focus on delivery challenges, targeting strategies, and translational opportunities.
Understanding the interactions between nanoengineered particles and biological systems is crucial for advancing targeted therapies. When nanoparticles are introduced to biological fluids, they acquire a “biomolecular corona” composed of adsorbed proteins, lipids, and nucleic acids. This corona significantly influences interactions with immune cells, impacting therapeutic efficacy and safety. Our early work identified person-specific biomolecular coronas on poly(ethylene glycol) (PEG)-coated nanoparticles, revealing that individual variations in plasma protein composition could predict nanoparticle association with immune cells in human blood. These findings underscore the complexity of using PEG-based nanoparticles across diverse populations (ACS Nano 2020, 14, 15723).
Building on this foundation, we investigated the immunogenic response to PEG in SARS-CoV-2 mRNA lipid nanoparticle (LNP) vaccines, observing substantial boosts in anti-PEG antibodies in recipients of the mRNA-1273 vaccine and, to a lesser extent, the BNT162b2 vaccine (ACS Nano 2022, 16, 11769). These antibodies could alter the biodistribution of subsequent PEG-containing nanomedicines. Our recent work on pharmacokinetics of LNP-based mRNA vaccines in human blood has investigated the relationship between PEG-specific antibodies and mRNA vaccine circulation (ACS Nano 2024, 18, 27077). Furthermore, we developed an ex vivo human leukemia blood model to examine person-specific targeting of PEGylated nanoparticles functionalized with anti-CD20, achieving promising targeting efficiency while minimizing off-target uptake by phagocytes. This personalized approach highlights the potential of tailored nanoparticle therapies, addressing key barriers to clinical translation in precision oncology (ACS Nano 2024, 18, 29021). In this talk, I will present our insights from these studies (Nature Reviews Immunology 2023, 23, 135; Nature Nanotechnology 2025, 20, 576), underscoring the implications of patient-specific interactions in advancing mRNA vaccine and therapeutics.