mRNA Vaccine Based on Porous Silica Nanoparticles Demonstrates Long-term Safety in Human Phase 1 Trial for One Year
Background
Messenger RNA (mRNA) vaccines proved their capability for rapid antigen design and production during the COVID-19 pandemic. However, mRNA is vulnerable to degradation by bodily enzymes before it can enter cells intact, making effective delivery technology essential.
While Lipid Nanoparticles (LNP) are the current standard, they face limitations such as the need for ultra-low temperature cold chains, potential liver toxicity from systemic circulation, and allergic reactions to PEG. This has driven the search for next-generation nanocarriers that ensure thermal stability and promote localized delivery at the injection site to reduce systemic side effects.
Among these, Mesoporous Silica Nanopabilities (MSN) have gained attention due to their uniform pore structure and excellent biocompatibility, physically protecting nucleic acids within the pores. However, clinical evidence regarding whether silica carriers can safely degrade and be excreted in humans while inducing effective immune responses has been lacking.
Key Findings
Korean researchers have released Phase 1 clinical results for LEM-mR203, an mRNA SARS-CoV-2 receptor binding domain (RBD) booster vaccine candidate utilizing the mesoporous silica nanoparticle technology, DegradaBALL. The study was designed as a randomized, double-blind, placebo-controlled, dose-escalation trial. Twenty healthy Korean adult volunteers were divided into 40μg, 100μg, and placebo groups, receiving a single intramuscular injection.
Participants were monitored for up to 366 days post-vaccination, with detailed analysis of local and systemic adverse events, hematological values, neutralizing antibody titers, and cell-mediated immune responses. Both the 40μg and 100μg groups showed excellent tolerability. Observed adverse events were mostly mild (Grade 1) injection-site pain, and the frequency of systemic adverse events was extremely low. No fever, serious adverse events (SAE), or adverse events of special interest (AESI) were reported. Transient, asymptomatic decreases in white blood cell counts occurred in some subjects but were observed in the placebo group as well and resolved naturally without sequelae.
In the immunogenicity assessment, 85% of participants were in a pre-immune state, already possessing nucleocapsid antibodies at enrollment. Anti-RBD Immunoglobulin G (IgG) levels remained stable at baseline levels through Day 3le66. Due to existing natural infection or prior vaccination, a significant booster-induced spike in antibodies was not prominent, and neutralizing antibody titers against the Kappa variant (B.1.617.1) gradually decreased over time, consistent with typical mRNA vaccine antibody kinetics.
ELISpot analysis showed that the 100μg high-dose group induced interferon-gamma (IFN-γ) secreting T-cell responses. No interleukin-4 (IL-4) skewing, an indicator of Type 2 helper T (Th2) response, was observed, indicating the formation of a safe, Th1-centered cellular immune environment without the risk of exacerbating respiratory diseases triggered by Th2 overactivation.
Significance and Outlook
These Phase 1 results demonstrate that mRNA vaccines using silica-based inorganic nanoparticle carriers can maintain long-term safety in the human body for over a year. This presents an alternative pathway to the silica nano-platform in the field of nucleic acid therapeutic delivery, which has relied heavily on LNP technology. Given the relatively high room-temperature stability of silica formulations, this opens a useful option for developing vaccines for developing countries where cold chain distribution is vulnerable.
While human applicability has been confirmed, clear challenges remain. As this was a small-scale exploratory study limited to 20 participants, safety reconfirmation in larger populations is required. Since most participants already possessed COVID-19 immunity, the sample size was limited in statistically proving the pure booster immune enhancement effect of a single dose. Future follow-up studies are needed to objectively prove antibody induction capability through expanded clinical trials including unvaccinated groups or those carrying the latest variant antigens.
PURPOSE: mRNA vaccines require an effective delivery system for intracellular uptake, and alternative carriers with improved stability and tolerability remain of continued interest. This study evaluated the safety, tolerability, and exploratory immunogenicity of LEM-mR203, an mRNA SARS-CoV-2 receptor binding domain (RBD) booster vaccine formulated with DegradaBALL, a mesoporous silica nanoparticle-based delivery system developed to improve mRNA stability and enable localized delivery. METHODS: In a randomized, double-blind, placebo-controlled, dose-escalation phase 1 study, a single intramuscular dose of LEM-mR203 (40<0xC2><0xA0>μg or 100<0xC2><0xA0>μg) or placebo was administered to 20<0xC2><0xA0>healthy Korean adult volunteers. Safety endpoints included solicited and unsolicited adverse events (AEs), serious AEs, and AEs of special interest. Exploratory immunogenicity comprised anti-RBD antibody concentrations and neutralizing antibody (Nab) titers through Day 366, together with interferon-γ (IFN-γ)/interleukin-4 (IL-4) ELISpot responses. RESULTS: LEM-mR203 was well tolerated at both dose levels, with mild (Grade 1) injection-site reactions and infrequent solicited systemic AEs; no fever, serious AEs, or AEs of special interest were reported. Transient, asymptomatic decreases in white blood cell count occurred across active and placebo groups and resolved without sequelae. In this pre-immune cohort (85% anti-nucleocapsid reactive), anti-RBD IgG was maintained through Day 366 without a clear booster-induced increase and Nab titers against the Kappa variant (B.1.617.1) waned, consistent with known mRNA vaccine kinetics. Exploratory ELISpot results suggested an IFN-γ-oriented cellular response in the 100<0xC2><0xA0>μg group, without evidence of IL-4/Th2 skewing. CONCLUSION: A single booster dose of LEM-mR203 was well tolerated, with no major safety concerns over 366 days, and with exploratory cellular responses suggesting an IFN-γ-oriented profile without Th2 skewing. Given the small sample size and high pre-e
This study proves that mesoporous silica, a biodegradable inorganic material, can serve as a safe clinical alternative in the drug delivery market currently dominated by lipid nanoparticles. Silica materials offer the advantage of reducing the complex formulation processes and precise lipid synthesis costs characteristic of lipid carriers. Improved distribution and storage stability would directly lead to reduced pharmaceutical logistics costs.
Industrially, this can be applied beyond infectious disease vaccines to areas requiring localized drug delivery, such as cancer vaccines or in vivo gene editing therapeutics. Unlike LNPs, which tend to accumulate in the liver, optimizing formulations to act selectively on lymph nodes at the injection site can induce powerful T-cell responses while suppressing systemic side effects. This provides a foothold for vaccine manufacturers to implement diversification strategies for delivery carriers, bypassing LNP patent barriers and securing independent intellectual property.