Smart ingestible devices: Orally delivering macromolecules and beyond

Oral administration of macromolecule drugs is traditionally challenging due to the harsh environment these navigate through gastrointestinal tract and resultant low blood adsorption. Recently, a series work has demonstrated use smart ingestible devices comprising an intricate design drug-loaded vehicle that can adjust direction accurately pierce into tissue wall, thus delivering with high efficiency. Main textBioactive macromolecules, such as antibodies peptides, have emerged one most promising therapeutic agents revolutionize methods disease treatment. Delivery biomacromolecules crucial yet their intrinsic susceptibility biodegradation. Among all delivery routes, oral offers non-invasive patient-preferable strategy. However, orally administered suffer from extreme conditions in (GI) including pH, richness protease, mucus layer, cellular junction, which together result limited bloodstream adsorption.1Dubey S.K. Parab S. Dabholkar N. Agrawal M. Singhvi G. Alexander A. Bapat R.A. Kesharwani P. peptide delivery: challenges way ahead.Drug Discov. Today. 2021; 26: 931-950Crossref PubMed Scopus (19) Google Scholar,2Lamson N.G. Berger Fein K.C. Whitehead K.A. Anionic nanoparticles enable proteins by enhancing intestinal permeability.Nat. Biomed. Eng. 2020; 4: 84-96Crossref (102) Scholar Although preclinical strategies been proposed circumvent restrictions, absorption enhancers, enzymatic degradation inhibitors, mucoadhesive polymers, various forms nanocarriers, currently achieved bioavailability biomacromolecule still far satisfactory.3Anselmo A.C. Gokarn Y. Mitragotri Non-invasive for biologics.Nat. Rev. Drug 2019; 18: 19-40Crossref (246) Therefore, novel systems safe efficient are highly desired.In recent years, substantial progress based on microcarriers, microparticles, micromotors, microneedle devices. In particular, consist variety above functional units execute multiple instructions programmatically after being delivered target site, attracted extensive attention since proposed. A research group led Traverso Langer Massachusetts Institute Technology (MIT) reported February 2019 Science leopard-tortoise-inspired insulin capsule containing compressed millipost, also called self-orienting millimeter-scale applicator (SOMA) (Figure 1A).4Abramson Caffarel-Salvador E. Khang Dellal D. Silverstein Gao Frederiksen M.R. Vegge Hubálek F. Water J.J. et al.An system macromolecules.Science. 363: 611-615Crossref (180) Upon reaching patient’s stomach, could reorient automatically inject millipost stomach releasing at controlled rate bloodstream. addition delivery, they made another breakthrough wall small intestine. Writing October same year Nature Medicine, developed luminal unfolding injector (LUMI) 1B).5Abramson Soares V. Minahan Tian R.Y. Lu X. Kim Wainer J. al.A macromolecules.Nat. Med. 25: 1512-1518Crossref (92) The had polymer shell survive acid stomach. intestine, ruptured rise pH ejected three folding arms inside. Each arm array that, force actuation, penetrated mucosa released or other drugs. Despite fact SOMA LUMI capsules function well demonstrated, there remained some essential limitations, dose capacity (300–700 μg per pill), absolute (10% less), requirement enduring degradative-enzyme-filled GI fluid before drug injection.To solve issues, team recently presented new version Biotechnology redesigning actuation 1C).6Abramson Jensen B. Poulsen Mouridsen Jespersen M.O. Kirk R.K. Windum al.Oral systemic monoclonal antibodies, peptides molecules using gastric auto-injectors.Nat. Biotechnol. https://doi.org/10.1038/s41587-021-01024-0Crossref (12) pill, liquid-injecting (L-SOMA), upgraded loading 4 mg enabled liquid formulations bioavailable submucosa. It consisted drug, injection needle, plunger squeeze out capsule. needle were locked place pellets isomalt. As pill entered moist began dissolve, thrusting while squeezed Once was fully released, pulled back eventually expelled digestive tract. To assess efficacy, used deliver four commonly injectable drugs, recombinant human insulin, GLP-1 analogs, adalimumab, epinephrine, studies efficacies vivo swine model. Insulin, inactivated GLP-1, epinephrine L-SOMA be observed serum within 15 min, plasma exposure time adalimumab 1 h. dosed immediately hypoglycemia, adalimumab-dosed inactivated-GLP-1-dosed experienced measurable levels least 3 days, consistent half-lives total 28 31 L-SOMA-treated showed positive (over 90%). Overall, system, maximum concentrations similar standard subcutaneous injections 30 min up 80% few hours.Instead relying injecting insertion milliposts microneedles, Zhao colleagues, Nanjing University, intelligent magnetic-controlled robotic (MMR) device 1D).7Zhang Chen Fu Wang Magneto-responsive robots delivery.Adv. Mater. : e2104932.https://doi.org/10.1002/adma.202104932Crossref (26) Advanced Materials, introduced robot tips, separable connections, magnetic substrate. MMR taken aid commercial enteric capsules, it With presence its polarized substrate, tips reoriented overcoming obstacles, inserting tissue, encapsulated bioactive substances under specific field. addition, left continuously release drugs; substrate excreted safely. An test diabetic minipig model insulin-loaded MMRs induced magnet penetrate depth 500 μm control. Then glucose level treated minipigs found fall normal about 2 Additionally, when treating administration, slightly increased quickly recovered normoglycemia state. This study extended coupling external fields.Overall, improve efficiency biomacromolecules, large amount greatly promoted development this general principle comprises two approaches. One encapsulate transport them site is, structural vehicle, cases, remote control magnet, built-in vehicles drug. gradually bloodstream, separates absorbed body. Note enables physical microneedles thereby surpassing conventional diffusion process achieving higher adsorption Compared simple formulations, point biological macromolecules proteins, vaccines.8Drucker D.J. Advances therapeutics.Nat. 19: 277-289Crossref (201) While considering applications future clinical therapy, several issues need further addressed. First, complexity devices, optimization completely avoid obstruction risks should consideration. Second, sufficient trials needed safety, any possible adverse reactions humans ready enter market. Third, conceivable beyond cells (e.g., stem cells, probiotics, etc.) precisely sites direct encapsulation during manufacturing process, avoiding damage complex physiological environments.9Iacovacci Tamadon I. Kauffmann E.F. Pane Simoni Marziale L. Aragona Cobuccio Chiarugi Dario implantable intraperitoneal refilled capsules.Sci. Robot. 6: eabh3328https://doi.org/10.1126/scirobotics.abh3328Crossref (5) Scholar,10Yu Q. C. Shang Living materials regenerative medicine.Eng. Regener. 2: 96-104Google These living cargos maintain viability long-term storage enough cell potent performances. lie ahead, we believe rapid advances material science, robotics, industry boost beyond, would bring great hope countless patients. Bioactive desired. injection. hours. Instead fields. supported National Key Research Development Program China ( 2020YFB1313100 ), Natural Foundation 22002018 Innovative Team High-level Local University Shanghai , Professor Special Appointment (Eastern Scholar) Institutions Higher Learning SSH1340011 ).