• Antibacterial and cell-instructive chitosan/NeoNectin hydrogels crosslinked via click chemistry enable stiffness-independent osteogenic differentiation
  Hybrid materials
  Daniel Cabrerizo-Aguado, Federica Barbugian, Maria-Pau Ginebra, Xinru Wang, David Baker, Jose Maria Manero, Jordi Guillem-Marti. Carbohydrate polymers, 2026 | doi:https://doi.org/10.1016/j.carbpol.2026.125392
  
  PDF

Lab-Led

• Bond-centric modular design of protein assemblies
  Hybrid materials
  Shunzhi Wang, Andrew Favor, Ryan Kibler, Joshua Lubner, Andrew Borst, Nicolas Coudray, Rachel Redler, Huat Thart Chiang, Will Sheffler, Yang Hsia, Neville Bethel, Zhe Li, Damian C. Ekiert, Gira Bhabha, Lilo Pozzo, David Baker. Nature Materials, 2025 | doi:10.1101/2024.10.11.617872
  
  Abstract

  Directional interactions that generate regular coordination geometries are a powerful means of guiding molecular and colloidal self-assembly, but implementing such high-level interactions with proteins remains challenging due to their complex shapes and intricate interface properties. Here we describe a modular approach to protein nanomaterial design inspired by the rich chemical diversity that can be generated from the small number of atomic valencies. We design protein building blocks using deep learning-based generative tools, incorporating regular coordination geometries and tailorable bonding interactions that enable the assembly of diverse closed and open architectures guided by simple geometric principles. Experimental characterization confrms the successful formation of more than 20 multicomponent polyhedral protein cages, two-dimensional arrays and three-dimensional protein lattices, with a high (10%–50%) success rate and electron microscopy data closely matching the corresponding design models. Due to modularity, individual building blocks can assemble with diferent partners to generate distinct regular assemblies, resulting in an economy of parts and enabling the construction of reconfgurable networks for designer nanomaterials.

  PDF

Collaborator-Led

• Rapid and Inexpensive Image-Guided Grayscale Biomaterial Customization via LCD Printing
  Hybrid materials
  Francis RM, Kopyeva I, Lai N, Yang S, Filteau JR, Wang X, Baker D, DeForest CA.
  J Biomed Mater Res A, 2025 | doi:10.1002/jbm.a.37897
  
  Abstract

  Hydrogels are an important class of biomaterials that permit cells to be cultured and studied within engineered microenvironments of user-defined physical and chemical properties. Though conventional 3D extrusion and stereolithographic (SLA) printing readily enable homogeneous and multimaterial hydrogels to be formed with specific macroscopic geometries, strategies that further afford spatiotemporal customization of the underlying gel physicochemistry in a non-discrete manner would be profoundly useful toward recapitulating the complexity of native tissue in vitro. Here, we demonstrate that grayscale control over local biomaterial biochemistry and mechanics can be rapidly achieved across large constructs using an inexpensive (~$300) and commercially available liquid crystal display (LCD)-based printer. Template grayscale images are first processed into a “height-extruded” 3D object, which is then printed on a standard LCD printer with an immobile build head. As the local height of the 3D object corresponds to the final light dosage delivered at the corresponding xy-coordinate, this method provides a route toward spatially specifying the extent of various dosage-dependent and biomaterial, forming/modifying photochemistries. Demonstrating the utility of this approach, we photopattern the grayscale polymerization of poly(ethylene glycol) (PEG) diacrylate gels, biochemical functionalization of agarose- and PEG-based gels via oxime ligation, and the controlled 2D adhesion and 3D growth of cells in response to a de novo-designed α5β1-modulating protein via thiol-norbornene click chemistry. Owing to the method’s low cost, simple implementation, and high compatibility with many biomaterial photochemistries, we expect this strategy will prove useful toward fundamental biological studies and functional tissue engineering alike.

  PDF

• Directing polymorph specific calcium carbonate formation with de novo protein templates
  Hybrid materials
  Davila-Hernandez FA, Jin B, Pyles H, Zhang S, Wang Z, Huddy TF, Bera AK, Kang A, Chen CL, De Yoreo JJ, Baker D.
  Nat Commun, 2023 | doi:10.1038/s41467-023-43608-1
  
  Abstract

  Biomolecules modulate inorganic crystallization to generate hierarchically structured biominerals, but the atomic structure of the organic-inorganic interfaces that regulate mineralization remain largely unknown. We hypothesized that heterogeneous nucleation of calcium carbonate could be achieved by a structured flat molecular template that pre-organizes calcium ions on its surface. To test this hypothesis, we design helical repeat proteins (DHRs) displaying regularly spaced carboxylate arrays on their surfaces and find that both protein monomers and protein-Ca supramolecular assemblies directly nucleate nano-calcite with non-natural {110} or {202} faces while vaterite, which forms first in the absence of the proteins, is bypassed. These protein-stabilized nanocrystals then assemble by oriented attachment into calcite mesocrystals. We find further that nanocrystal size and polymorph can be tuned by varying the length and surface chemistry of the designed protein templates. Thus, bio-mineralization can be programmed using de novo protein design, providing a route to next-generation hybrid materials.

  PDF

• Evolution of a designed protein assembly encapsulating its own RNA genome
  Hybrid materials Nanoparticles Synthetic Nucleocapsid Lab-led
  Butterfield GL, Lajoie MJ, Gustafson HH, Sellers DL, Nattermann U, Ellis D, Bale JB, Ke S, Lenz GH, Yehdego A, Ravichandran R, Pun SH, King NP, Baker D.
  Nature, 2017 | doi:10.1038/nature25157
  
  Abstract

  The challenges of evolution in a complex biochemical environment, coupling genotype to phenotype and protecting the genetic material, are solved elegantly in biological systems by the encapsulation of nucleic acids. In the simplest examples, viruses use capsids to surround their genomes. Although these naturally occurring systems have been modified to change their tropism and to display proteins or peptides, billions of years of evolution have favoured efficiency at the expense of modularity, making viral capsids difficult to engineer. Synthetic systems composed of non-viral proteins could provide a ‘blank slate’ to evolve desired properties for drug delivery and other biomedical applications, while avoiding the safety risks and engineering challenges associated with viruses. Here we create synthetic nucleocapsids, which are computationally designed icosahedral protein assemblies with positively charged inner surfaces that can package their own full-length mRNA genomes. We explore the ability of these nucleocapsids to evolve virus-like properties by generating diversified populations using Escherichia coli as an expression host. Several generations of evolution resulted in markedly improved genome packaging (more than 133-fold), stability in blood (from less than 3.7% to 71% of packaged RNA protected after 6 hours of treatment), and in vivo circulation time (from less than 5 minutes to approximately 4.5 hours). The resulting synthetic nucleocapsids package one full-length RNA genome for every 11 icosahedral assemblies, similar to the best recombinant adeno-associated virus vectors. Our results show that there are simple evolutionary paths through which protein assemblies can acquire virus-like genome packaging and protection. Considerable effort has been directed at ‘top-down’ modification of viruses to be safe and effective for drug delivery and vaccine applications; the ability to design synthetic nanomaterials computationally and to optimize them through evolution now enables a complementary ‘bottom-up’ approach with considerable advantages in programmability and control.

  PDF