Aug 2026· Journal of the American Chemical Society· Vol 148 32, pp.
34639-34654
· 0 citations· 43 references
Medicine
TL;DR
This work presents a metabolically targeted, bioorthogonal-activated delivery strategy to address the selectivity and efficiency limitations of current mRNA medicines, providing a promising platform for precision oncology.
Abstract
Lipid nanoparticle (LNP)-mediated mRNA delivery has emerged as a powerful therapeutic modality, yet its clinical translation in oncology remains constrained by inherent hepatic tropism and inefficient endosomal escape. These limitations necessitate high-dose administration, which triggers lipid-associated toxicity and off-target protein expression in the liver. To overcome these barriers, we report a cleavable silyl-ether-based bioorthogonally activatable LNP platform, termed SiLNP, that enables tumor-specific activation and cytosolic mRNA release. We engineered ionizable lipids incorporating silyl ether structural fuses that respond to a phenylalanine trifluoroborate (Phe-BF3) trigger. This system leverages the upregulated transporter LAT-1 to actively import Phe-BF3 into tumor cells, where it triggers lipid desilylation and rapid cargo release. In vitro, SiLNPs demonstrated controllable external control over mRNA expression, achieving a 44-fold enhancement in mRNA expression compared to standard SM-102 LNPs with a 10-fold activation-to-silent ratio. In immunologically "cold" B16-F10 melanoma models, SiLNPs encoding the N-terminal domain of gasdermin D (GDNT) induced tumor-specific pyroptosis, resulting in tumor growth inhibition without detectable systemic toxicity. Furthermore, this platform demonstrated versatility by delivering immunomodulatory mRNAs, including IL-2 and Cxcl9. Taken together, this work presents a metabolically targeted, bioorthogonal-activated delivery strategy to address the selectivity and efficiency limitations of current mRNA medicines, providing a promising platform for precision oncology.
A ligand-mediated lipid reprogramming approach that repurposes chemically defined, liver-tropic, ionizable lipids (lipidoids) for mRNA delivery beyond the liver, and achieves outperformed efficacy and therapeutic potential in lung-specific genome editing relative to SORT-constructed 2-t6b LNP system.
mRNA-based nucleic acid therapeutics have gained significant attention and undergone extensive clinical investigation since the FDA's approval of Spikevax and Comirnaty for the treatment of SARS-CoV-2. Lipid nanoparticles (LNPs) are currently the most advanced delivery system for delivering mRNA in vivo. However, concerns persist regarding the tolerability of their repeated use due to lipid accumulation. Over time, lipids have been optimized through the introduction of enzymatically degradable ester linkers. Yet, this modification alone does not fully address lipid clearance from the body. To mitigate these concerns, we have designed a library of novel ionizable lipids that incorporates two nitrogen atoms within the lipid backbone. We hypothesize that the LNPs with these lipids can be potentially administered at lower dosages while maintaining the same payload delivery and translation efficiency. In this study, we identified five lead LNPs that exhibited remarkable transfection efficiency without cytotoxic effects in vitro. We further optimized the LNP formulations by incorporating various cholesterol analogs to fine-tune translation performance. Upon analyzing the endocytic and intracellular pathways of the lead LNPs, we found that multiple pathways were involved in delivering the payload to the cell. This set of novel lipids holds great promise for mRNA delivery and warrants further investigation.
Vishnu Sriram, V. Phatangare, Joo-Youp Lee· Biomaterials Science· 0 citations
Lipid nanoparticles (LNPs) are highly modular drug nanocarriers that have significantly progressed in the development and application of novel RNA therapeutics. While instrumental in current vaccine and hepatic gene therapy applications, extrahepatic LNP delivery remains a challenging hurdle, severely limiting clinical applications for individualized therapies that require cellular- and tissue-specific enrichment. Novel platform development remains needed to generate targeted LNPs capable of modeling targeted uptake in vitro prior to in vivo applications. Herein, we developed and utilized an antibody-based targeting bispecific-LNP (TbsAb-LNP) platform simultaneously binding LNP polyethylene glycol motifs and desired cell surface markers. By colocalizing TbsAb-LNP complexes with desired cell surface markers, we enable mRNA-LNP accumulation in the desired cell types. We additionally assessed the endosomal efficiency kinetics of TbsAb-LNP complexes generated at various bispecific loading ratios in a Galectin-9 in vitro expression model. Leveraging this facile and modular platform that eliminates the need for complex chemical conjugation approaches, we successfully achieved targeted LNP delivery to xhuCD3-expressing lymphoblasts and xmTfR1-expressing cell lines in vitro as well as xmTfR1-expressing cells in vivo. Enrichment of TbsAb-LNPs to splenic cells demonstrates the potential utility of this platform for clinical vaccine and T-cell delivery applications.
J. C. Hickey, Tracoyia Roach, Britteny Cassaidy et al.· Molecular Pharmaceutics· 0 citations
A critical challenge in the bench-to-bedside translation of controlled drug release strategies is the sharp decline in reaction efficiency as biological complexity increases. A platform capable of maintaining bioorthogonal-like drug release─remaining minimally perturbed by physiological environments─would address an unmet clinical need. This is particularly relevant for radiotherapy-mediated drug release, where the oxidative activation of prodrugs is often compromised by the rapid quenching of reactive intermediates in vivo. Herein, we engineer a hafnium-based nanoscale metal-organic layer platform that leverages a unique "surface-confinement effect" to overcome this challenge. By covalently tethering prodrugs to the Hf-nMOLs surface, we constructed two-dimensional nanoreactors that spatially localize the activation process within an interface enriched with reactive species. This design effectively insulates the activation step from biological scavengers, ensuring efficient payload release efficiency across increasing biological complexity. When loaded with the topoisomerase I inhibitor Exatecan, the Hf-nMOLs system achieved an intratumoral drug-release G-value of 568 nM·Gy-1, resulting in potent radiosensitization and significant tumor-growth suppression under low-dose X-ray irradiation. This work presents a versatile strategy for robust radio-chemotherapeutic combinations, achieving the simultaneous release of diverse payloads activated by radiotherapy. Our findings also suggest that engineering nanoscale surface confinement may provide a generalizable materials strategy to help confer bioorthogonality to otherwise labile activation reactions.
Zhiyu Tu, Ziyang Sang, Yang Xu et al.· Journal of the American Chem...· 0 citations
The integration of rational material design, high-throughput screening, artificial intelligence, and interdisciplinary collaboration will be essential to advance next-generation targeted in vivo mRNA cell therapies toward clinical translation.
Danyang Wang, Yumin Li, Jinfeng Deng et al.· Drug Delivery· 0 citations
Gene-targeted therapies are of considerable interest for targeting multiple "undruggable" oncogenes. However, their therapeutic efficacy is largely hampered by off-target toxicity and inherent tumor heterogeneity. Herein, we describe a logic-responsive superspherical nucleic acid (SSNA) with on-demand, activatable functionality that enables tumor-specific multiplexed gene silencing for efficient cancer therapy. The SSNA architecture features a nuclease-resistant spherical nucleic acid core densely coated with a Y-shaped DNA circuit shell that selectively responds to apurinic/apyrimidinic endonuclease 1 (APE1), a biomarker overexpressed in tumor cytoplasm. Upon intracellular APE1-triggered shell disassembly, the SSNA enables the controlled release of split antisense oligonucleotides targeting thymidine kinase 1 (TK1) mRNA and DNAzymes that cleave survivin mRNA. Both in vitro and in vivo results demonstrated robust dual-gene silencing of TK1 and survivin at both transcriptional and translational levels, accompanied by exceptional tumor specificity and minimal off-target effects. Notably, in a murine MCF-7 xenograft model, SSNA significantly suppressed tumor growth and extended median survival by an impressive 70% compared to single-target interventions. By integrating tumor-specific activation with multiplexed gene silencing, such an SSNA platform offers a powerful and versatile approach for advancing next-generation precision cancer therapies.
Xian-Ming Guo, Mei-Ling Zhao, Xia Yang et al.· Angewandte Chemie· 0 citations
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