Engineered modular biomaterial logic gates for environmentally triggered therapeutic delivery


The successful transport of drug- and cell-based therapeutics to diseased sites represents a major barrier in the development of clinical therapies. Targeted delivery can be mediated through degradable biomaterial vehicles that utilize disease biomarkers to trigger payload release. Here, we report a modular chemical framework for imparting hydrogels with precise degradative responsiveness by using multiple environmental cues to trigger reactions that operate user-programmable Boolean logic. By specifying the molecular architecture and connectivity of orthogonal stimuli-labile moieties within material cross-linkers, we show selective control over gel dissolution and therapeutic delivery. To illustrate the versatility of this methodology, we synthesized 17 distinct stimuli-responsive materials that collectively yielded all possible YES/OR/AND logic outputs from input combinations involving enzyme, reductant and light. Using these hydrogels we demonstrate the first sequential and environmentally stimulated release of multiple cell lines in well-defined combinations from a material. We expect these platforms will find utility in several diverse fields including drug delivery, diagnostics and regenerative medicine.

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Figure 1: Rationally designed cross-linker architecture enables logic-based material degradation.
Figure 2: Engineered cross-linkers respond to environmental input combinations on the molecular level.
Figure 3: Logic-gated biomaterials exhibit programmable degradation in response to environmentally presented input combinations.
Figure 4: Logic-based doxorubicin delivery enhances specificity of HeLa cell death in the presence of multiple disease-state hallmarks.
Figure 5: Sequential and spatiotemporally varied delivery of small molecules and cells from gels following logic-based response to environmental cues.


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The authors thank B. Hayes and B. Torok-Storb for gifting the hS5 cells, S. Adelmund for synthesizing and supplying BCN-OSu, E. Ruskowitz for useful discussion involving the DOX studies, as well as K. Anseth, D. Tirrell, S. Pun and B. Ratner for constructive comments during the preparation of this manuscript. The authors acknowledge support from S. Edgar at the University of Washington (UW) Mass Spectrometry Center, D. Prunkard at the UW Pathology Flow Cytometry Core Facility, and N. Peters and support from the NIH to the UW W. M. Keck Microscopy Center (S10 OD016240). This work was supported by a University of Washington Faculty Startup Grant (to C.A.D.) and a National Science Foundation CAREER Award (DMR 1652141, to C.A.D.).

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B.A.B. and C.A.D. conceived and designed the experiments. B.A.B., M.P.C., C.K.A. and J.A.S. performed the experiments. B.A.B. and C.A.D. analysed the data and prepared the figures. B.A.B. and C.A.D. wrote the paper.

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Correspondence to Cole A. DeForest.

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Badeau, B., Comerford, M., Arakawa, C. et al. Engineered modular biomaterial logic gates for environmentally triggered therapeutic delivery. Nature Chem 10, 251–258 (2018).

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