Ana Jaklenec

Recent advances in messenger RNA (mRNA) vaccine technologies have enabled rapid responses to emerging infectious diseases and accelerated translation from antigen design to clinical deployment; however, their widespread implementation remains constrained by formulation instability, cold-chain dependence, multi-dose adherence challenges, and limited mechanisms for reliable verification of administration. These barriers reflect product-level and systems-level limitations rather than intrinsic deficiencies in mRNA efficacy, motivating the development of integrated delivery platforms that couple stability, dosing control, and verification within a single pharmaceutical product. Microneedle patch technologies address these challenges by combining intradermal delivery with solid-state formulation, stabilizing lipid nanoparticle (LNP)-encapsulated mRNA in dry matrices and enabling minimally invasive access to immunologically active skin layers, thereby reducing reliance on injection technique and cold-chain logistics. Advances in microneedle design and fabrication further enable spatial and temporal control of material deposition in the skin, supporting programmable release profiles, such as single-administration prime-boost strategies, as well as passive intradermal encoding of vaccination records. This review examines the design principles, formulation strategies, and translational considerations underlying microneedle patch-based delivery of mRNA vaccines, with a focus on dissolving and stimuli-responsive systems compatible with LNP formulations, mechanisms of intradermal transport and immune activation, solid-state stabilization approaches that preserve mRNA integrity, and emerging methods for embedding optically readable markers to enable administration verification independent of external records. Manufacturing scalability, quality control, and regulatory considerations are also discussed, emphasizing the need to treat formulation and fabrication as coupled design variables, and positioning microneedle patches as integrated vaccine products whose real-world performance is determined by the interplay of formulation, delivery, and manufacturing decisions.

Enteric pathogens are a major contributor to the global disease burden, necessitating vaccines capable of inducing robust gastrointestinal mucosal immunity. Achieving this response is especially challenging with inactivated or subunit vaccines, which lack the ability of live-attenuated formulations to mimic the natural infection process needed to induce strong intestinal mucosal immunity. Specifically, the inactivated polio vaccine (IPV), administered parenterally, elicits strong systemic immunity but fails to induce the mucosal IgA responses required to fully block poliovirus transmission, a critical step toward complete eradication. To address this limitation, we developed a clinically translatable and scalable nanoparticle-based intestinal mucosal adjuvant by encapsulating Am80, a small hydrophobic molecule known to promote intestinal mucosal immunity, within nanoparticles (NPs) designed for lymph node delivery, without requiring antigen modification, encapsulation, or adsorption. Encapsulation in NPs eliminated the need for the use of organic solvents, reduced toxicity, and prevented degradation, while lipid nanoparticles (Am80-LNPs) were engineered for sustained release over 3 to 5 days with high encapsulation efficiency (78 ± 9%). Cy5-labeled Am80-LNPs localized to draining lymph nodes within 6 hours and were retained for up to 72 hours. Coadministration of Am80-LNPs with the licensed IPV-2 in a Wistar rat model significantly boosted IPV-2–specific fecal IgA by 20-fold compared to IPV-2 alone and threefold over free Am80. These findings demonstrate that Am80-LNPs significantly enhance IPV-2–specific mucosal immunity in vivo and suggest their potential as a potent mucosal adjuvant against other enteric pathogens.

Cold chain storage requirements limit the accessibility of mRNA vaccines and therapeutics more broadly within the developing world. Polymer microneedles are a promising alternative for overcoming challenges associated with cold chain distribution and vaccine storage, and have additional advantages in ease of application. Herein, we reveal the structural transformations and performance of mRNA‐loaded lipid nanoparticles (LNPs) during dehydration and rehydration within the polymer framework (PVPVA) employed for microneedle fabrication. Cryogenic transmission electron microscopy and in situ small‐angle x‐ray scattering revealed that the LNPs display partial inverse hexagonal packing of the self‐assembled lipid molecules, which can be recovered upon rehydration with sufficient polymer loading (polymer:mRNA > 320:1). The performance of the recovered LNPs is sensitive to polymer loading, and at low polymer loading (polymer:mRNA 32:1), the LNPs are unstable. LNPs of higher N/P ratios (mole ratio of protonatable amines to mole of phosphate groups from mRNA) were more robust to recovery due to improved mRNA encapsulation efficiency (∼20%–80%) and potentially lower loss of mRNA‐loaded carriers during processing (∼3‐fold lower coalescence signal). Balancing the polymer and mRNA loading yielded a 100‐fold increase in transfection for the optimized 5.4 N/P ratio Lipid‐5 system.

Malnutrition can severely compromise immune function, rendering populations more vulnerable to both communicable and non-communicable diseases. Here, we discuss food fortification and micronutrient supplementation programs that have been instrumental in mitigating malnutrition across Africa and in controlling disease spread, marking considerable advances in public health throughout the continent. Jaklenec, Yang et al. examine how malnutrition heightens disease susceptibility in Africa. They comment on the successes of food-fortification efforts to date and outline remaining barriers and future directions.