Robert Langer’s research while affiliated with Koch Institute for Integrative Cancer Research At MIT and other places

Oral drug delivery is a widely preferred method of drug administration due to its ease of use and convenience for patients. Localization of drug release in the gastrointestinal (GI) tract is important to treat localized diseases and maximize drug absorption. However, achieving drug localization in the dynamic GI tract is challenging. To address this challenge, we leveraged the geographic diversity of the GI tract by targeting its mucus layers, which coat the epithelial surfaces. These layers, composed of mucin glycoproteins, are synthesized with unique chemical compositions and expressed in different regions, making them ideal targets for drug localization. In this article, we identify cyclic peptides that bind selectively to MUC2 (in the intestines) and MUC5AC (in the stomach), serving as targeting ligands to these regions of the GI tract. We demonstrate the effectiveness of these peptides through in vitro, ex vivo, and in vivo experiments, showing that incorporating these targeting ligands can increase binding and selectivity 2-fold to the desired regions, thus potentially overcoming challenges with localizing drug distribution in oral delivery. These results indicate that cyclic peptides can be used to localize drug cargoes at certain sites in the body compared to free drugs.

The targeted delivery of immunotherapies to tumours using tumour-responsive nanomaterials is a promising area of cancer research with the potential to address the limitations of systemic administration such as on-target off-tumour toxicities and a lack of activity owing to the immunosuppressive tumour microenvironment (TME). Attempts to address these challenges include the design and functionalization of nanomaterials capable of releasing their cargoes in response to specific TME characteristics, thus facilitating the targeted delivery of immune-checkpoint inhibitors, cytokines, mRNAs, vaccines and, potentially, chimaeric antigen receptors as well as of agents that modulate the extracellular matrix and induce immunogenic cell death. In this Review, we describe these various research efforts in the context of the dynamic properties of the TME, such as pH, reductive conditions, reactive oxygen species, hypoxia, specific enzymes, high levels of ATP and locoregional aspects, which can be leveraged to enhance the specificity and efficacy of nanomaterial-based immunotherapies. Highlighting preclinical successes and ongoing clinical trials, we evaluate the current landscape and potential of these innovative approaches. We also consider future research directions as well as the most important barriers to successful clinical translation, emphasizing the transformative potential of tumour-responsive nanomaterials in overcoming the barriers that limit the activity of traditional immunotherapies, thus improving patient outcomes.

Establishing a robust and intimate mucosal interface that allows medical devices to remain within lumen-confined organs for extended periods has valuable applications, particularly for gastrointestinal theranostics. Here, we report the development of an electroadhesive hydrogel interface for robust and prolonged mucosal retention after electrical activation (e-GLUE). The e-GLUE device is composed of cationic polymers interpenetrated within a tough hydrogel matrix. An e-GLUE electrode design eliminated the need for invasive submucosal placement of ground electrodes for electrical stimulation during endoscopic delivery. With an electrical stimulation treatment of about 1 minute, the cationic polymers diffuse and interact with polyanionic proteins that have a relatively slow cellular turnover rate in the deep mucosal tissue. This mucosal adhesion mechanism increased the adhesion energy of hydrogels on the mucosa by up to 30-fold and enabled in vivo gastric retention of e-GLUE devices in a pig stomach for up to 30 days. The adhesion strength was modulated by polycationic chain length, electrical stimulation time, gel thickness, cross-linking density, voltage amplitude, polycation concentration, and perimeter-to-area ratio of the electrode assembly. In porcine studies, e-GLUE demonstrated rapid mucosal adhesion in the presence of luminal fluid and mucus exposure. In proof-of-concept studies, we demonstrated e-GLUE applications for mucosal hemostasis, sustained local delivery of therapeutics, and intimate biosensing in the gastrointestinal tract, which is an ongoing clinical challenge for commercially available alternatives, such as endoclips and mucoadhesive. The e-GLUE platform could enable theranostic applications across a range of digestive diseases, including recurrent gastrointestinal bleeding and inflammatory bowel disease.

Medical interventions often require timed series of doses, thus necessitating accurate medical record-keeping. In many global settings, these records are unreliable or unavailable at the point of care, leading to less effective treatments or disease prevention. Here we present an invisible-to-the-naked-eye on-patient medical record-keeping technology that accurately stores medical information in the patient skin as part of microneedles that are used for intradermal therapeutics. We optimize the microneedle design for both a reliable delivery of messenger RNA (mRNA) therapeutics and the near-infrared fluorescent microparticles that encode the on-patient medical record-keeping. Deep learning-based image processing enables encoding and decoding of the information with excellent temporal and spatial robustness. Long-term studies in a swine model demonstrate the safety, efficacy and reliability of this approach for the co-delivery of on-patient medical record-keeping and the mRNA vaccine encoding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This technology could help healthcare workers make informed decisions in circumstances where reliable record-keeping is unavailable, thus contributing to global healthcare equity.

The “Voices” under this Perspective underline the importance of interdisciplinary collaboration and partnerships across several disciplines, such as medical science and technology, medicine, bioengineering, and computational approaches, in bridging the gap between research, manufacturing, and clinical applications. Effective communication is key to bridging team gaps, enhancing trust, and resolving conflicts, thereby fostering teamwork and individual growth toward shared goals. Drawing from the success of the COVID-19 vaccine development, we advocate the application of similar collaborative models in other complex health areas such as nanomedicine and biomedical engineering. The role of digital technology and big data in healthcare innovation is highlighted along with the necessity for specialized education in collaborative practices. This approach is decisive in advancing healthcare solutions, leading to improved treatment and patient outcomes.