Robotic pills for gastrointestinal-tract-targeted oral mRNA delivery

mRNA has become a new class of therapeutics and vaccines that possess high efficacy for the treatment and prevention of a variety of diseases. Recently, a team led by Professors Traverso and Langer, pioneers and leaders in the field of drug delivery and biomedical devices, reported the design and use of robotic pills for gastrointestinal-tract-targeted oral mRNA delivery, opening up a new avenue for the oral mRNA medicines. mRNA has become a new class of therapeutics and vaccines that possess high efficacy for the treatment and prevention of a variety of diseases. Recently, a team led by Professors Traverso and Langer, pioneers and leaders in the field of drug delivery and biomedical devices, reported the design and use of robotic pills for gastrointestinal-tract-targeted oral mRNA delivery, opening up a new avenue for the oral mRNA medicines. Nucleic-acid-based medicines, especially mRNA-based therapeutics and vaccines, have been shown to exhibit high efficacy in the treatment and prevention of a variety of diseases. The pivotal role of mRNA vaccines in controlling the COVID-19 pandemic highlights the great potential of mRNA-based medicines.1Jain S. Venkataraman A. Wechsler M.E. Peppas N.A. Messenger RNA-based vaccines: Past, present, and future directions in the context of the COVID-19 pandemic.Adv. Drug Deliv. Rev. 2021; 179: 114000Google Scholar This has stimulated the rapid development of various mRNA-based biomedical applications including vaccines, immunotherapy, gene editing, and functional protein restoration in tackling different diseases. Compared to conventional vaccines, mRNA vaccines have extraordinarily high efficacy and a much shorter development cycle, which is crucial for quickly slowing down the spread of highly contagious viruses such as SARS-CoV-2, which originally caused the COVID-19 pandemic. While the current mRNA medicines are predominantly administrated via intravenous or subcutaneous injection, novel mRNA medicines that can be administrated to patients by oral dosage forms are very much preferred.1Jain S. Venkataraman A. Wechsler M.E. Peppas N.A. Messenger RNA-based vaccines: Past, present, and future directions in the context of the COVID-19 pandemic.Adv. Drug Deliv. Rev. 2021; 179: 114000Google Scholar Recently, Abramson et al. demonstrated the possibility of the direct delivery of mRNA-loaded polymeric nanoparticles into the gastric submucosa via orally administrated robotic pills (Figure 1).2Abramson A. Kirtane A.R. Shi Y. Zhong G. Collins J.E. Tamang S. Ishida K. Hayward A. Wainer J. Rajesh N.U. et al.Oral mRNA delivery using capsule-mediated gastrointestinal tissue injections.Matter. 2022; 5: 975-987https://doi.org/10.1016/j.matt.2021.12.022Google Scholar To facilitate the cellular uptake of mRNA, they first screened a library of hybrid branched poly(β-amino esters) (PBAE) nanoparticles for the encapsulation and cellular delivery of mRNA. The top-performing mRNA-loaded PBAE nanoparticles were then lyophilized, concentrated, and filled into the robotic pill called Self-Orienting Millimeter-Scale Applicator (SOMA). Upon oral administration, the robotic pills quickly entered the stomach, where they could self-orient to allow the direct injection of mRNA nanoparticles into the stomach submucosa for robust mRNA expression, bypassing the natural barriers existing in the gastrointestinal (GI) tract. This study has led to a novel GI-tract-targeted oral delivery system for mRNA, holding great promise to promote the development of more convenient and patient-preferred oral mRNA therapeutics and vaccines. In addition to the oral delivery of mRNA, the SOMA robotic pills can also be used for the oral delivery of other macromolecules. The oral delivery strategy has the advantages of superior convenience and patient compliance.3Forbes D.C. Peppas N.A. Oral delivery of small RNA and DNA.J. Control. Release. 2012; 162: 438-445Google Scholar, 4Sharpe L.A. Daily A.M. Horava S.D. Peppas N.A. Therapeutic applications of hydrogels in oral drug delivery.Expert Opin. Drug Deliv. 2014; 11: 901-915Google Scholar, 5Wagner A.M. Gran M.P. Peppas N.A. Designing the new generation of intelligent biocompatible carriers for protein and peptide delivery.Acta Pharm. Sin. B. 2018; 8: 147-164Google Scholar For example, Abramson et al. previously described the oral delivery of insulins using the SOMA robotic pills.6Abramson A. Caffarel-Salvador E. Khang M. Dellal D. Silverstein D. Gao Y. Frederiksen M.R. Vegge A. Hubálek F. Water J.J. et al.An ingestible self-orienting system for oral delivery of macromolecules.Science. 2019; 363: 611-615Google Scholar In this study, the authors demonstrated the novel and creative design of the ingestible self-orienting system-SOMA robotic pills, which were inspired by the leopard tortoise’s ability to passively reorient. Thus, orally administrated robotic pills could rapidly reach the stomach and enable self-orientation to the preferred upright position, allowing the injection of insulin-loaded tips into the mucosa within 1 min, which was triggered by the dissolution of caramelized sucrose. The insulin loads were then released to the mucosa within 1 h of the dissolution of the tips. To expand the applications of the SOMA robotic pill system, Traverso, Langer, and their groups have implemented the oral delivery of systemic monoclonal antibodies, peptides, and small molecules using a new version of the SOMA robotic pills.7Abramson A. Frederiksen M.R. Vegge A. Jensen B. Poulsen M. Mouridsen B. Jespersen M.O. Kirk R.K. Windum J. Hubálek F. et al.Oral delivery of systemic monoclonal antibodies, peptides and small molecules using gastric auto-injectors.Nat. Biotechnol. 2022; 40: 103-109Google Scholar The new robotic pills could not only enable the oral delivery of drugs whose size range from small molecules to monoclonal antibodies but also achieve a maximum drug plasma concentration that is similar to the standard-of-care subcutaneous injection within 30 min after the oral administration. Besides the SOMA robotic pill system, Traverso and associates have also developed many other smart biomedical devices for the oral delivery of biologic drugs.8Byrne J. Huang H.-W. McRae J.C. Babaee S. Soltani A. Becker S.L. Traverso G. Devices for drug delivery in the gastrointestinal tract: A review of systems physically interacting with the mucosa for enhanced delivery.Adv. Drug Deliv. Rev. 2021; 177: 113926Google Scholar Instead of delivering the therapeutics to the stomach tissues, a new robotic pill system called luminal unfolding microneedle injector (LUMI), utilizing the tube-like geometry of the small intestine to provide plenty of points of contact with the tissues, was invented to deliver therapeutics to the intestinal tissues.9Abramson A. Caffarel-Salvador E. Soares V. Minahan D. Tian R.Y. Lu X. Dellal D. Gao Y. Kim S. Wainer J. et al.A luminal unfolding microneedle injector for oral delivery of macromolecules.Nat. Med. 2019; 25: 1512-1518Google Scholar Upon oral administration, the elegant design of this robotic pill allows the rapid propelling of dissolvable drug-loaded microneedles, located on three unfolding arms, into intestinal tissues. In another study, they designed a kirigami-inspired stent for the sustained delivery of therapeutics to the GI tract with maximal local drug efficacy and minimal potential systemic side effects.10Babaee S. Shi Y. Abbasalizadeh S. Tamang S. Hess K. Collins J.E. Ishida K. Lopes A. Williams M. Albaghdadi M. et al.Kirigami-inspired stents for sustained local delivery of therapeutics.Nat. Mater. 2021; 20: 1085-1092Google Scholar Therefore, a well-designed robotic pill system enables the oral delivery of mRNA to the GI tract, providing a simple and non-invasive approach for mRNA delivery, and might eventually benefit the rapid development of novel mRNA therapeutics and vaccines. The authors acknowledge the support from Harvard Medical School/Brigham and Women’s Hospital Department of Anesthesiology-Basic Scientist Grant (No. 2420 BPA075 to W.T.), the US METAvivor Early Career Investigator Award (No. 2018A020560 to W.T.), the Khoury Innovation Award (No. 2020A003219 to W.T.), the Gillian Reny Stepping Strong Center for Trauma Innovation Breakthrough Innovator Award (No. 113548 to W.T.), the American Heart Association (AHA) Collaborative Sciences Award (No. 2018A004190 to W.T.), the Farokhzad Family Distinguished Chair Foundation (W.T.), NIH grant (R01-EB022025 to N.A.P.), the Cockrell Family Chair Foundation (N.A.P.), the Institute for Biomaterials, Drug Delivery, and Regenerative Medicine (N.A.P.), and the UT-Portugal Collaborative Research Program (N.A.P.). W.T. and N.A.P. are on the Matter scientific advisory board. Oral mRNA delivery using capsule-mediated gastrointestinal tissue injectionsAbramson et al.MatterJanuary 31, 2022In BriefNucleic acid therapeutics and vaccines are only available as injectable formulations that generate discomfort and lead to low patient acceptance. To enable oral delivery, these therapeutics must avoid enzymatic degradation and bypass physical tissue barriers in the gastrointestinal tract. Here, the authors describe orally dosed pills capable of delivering nanoparticle formulations of nucleic acids with high transfection efficiencies via milli-needle injections into the gastric lining. This formulation-device combination results in gastric and systemic uptake in large and small animals, respectively. Full-Text PDF Open Archive