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Protein crystallization plays a central role in structural biology, with broad impact in pharmaceutical formulation, drug delivery, biosensing, and biocatalysis. Despite this importance, the process of protein crystallization remains poorly understood and highly empirical, with largely unpredictable crystal contacts, lattice packing arrangements, and space group preferences, and the programming of protein crystallization through precisely engineered sidechain-sidechain interactions across multiple protein-protein interfaces is an outstanding challenge. Here we develop a general computational approach to designing three-dimensional(3D) protein crystals with pre-specified lattice architectures at atomic accuracy that hierarchically constrains the overall degree of freedoms (DOFs) of the system. We use the approach to design three pairs of oligomers that can be individually purified, and upon mixing, spontaneously self-assemble into large 3D crystals (>100 micrometers). Small-angle X-ray scattering and X-ray crystallography show these crystals are nearly identical to the computational design models, with the design target F4132 and I432 space groups and closely corresponding overall architectures and protein-protein interfaces. The crystal unit cell dimensions can be systematically redesigned while retaining space group symmetry and overall architecture, and the crystals are both extremely porous and highly stable, enabling the robust scaffolding of inorganic nanoparticle arrays. Our approach thus enables the computational design of protein crystals with high accuracy, and since both structure and assembly are encoded in the primary sequence, provides a powerful new platform for biological material engineering.

Oncolytic virotherapy has currently emerged as a powerful therapeutic approach in cancer treatment. Although the history of using viruses goes back to the early 20th century, the approval of talimogene laherparepvec (T-VEC) in 2015 increased interest in oncolytic viruses (OVs). OVs are multifaceted biotherapeutic agents because they replicate in and kill tumor cells and augment immune responses by releasing immunostimulatory molecules from lysed cells. Despite promising results, some limitations hinder the efficacy of oncolytic virotherapy. The delivery challenges and the upregulation of checkpoints following oncolytic virotherapy also mediate resistance to OVs by diminishing immune responses. Furthermore, the localization of receptors of viruses in the tight junctions, interferon responses, and the aberrant expression of genes involved in the cell cycle of the virus, including their infection and replication, reduce the efficacy of OVs. In this review, we present different mechanisms of resistance to OVs and strategies to overcome them.

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