The
surface of proteins is heterogeneous with sophisticated but
precise hydrophobic and hydrophilic patches, which is essential for
their diverse biological functions. To emulate such distinct surface
patterns on macromolecules, we used rigid spherical synthetic dendrimers
(polyphenylene dendrimers) to provide controlled amphiphilic surface
patches with molecular precision. We identified an optimal spatial
arrangement of these patches on certain dendrimers that enabled their
interaction with human adenovirus 5 (Ad5). Patchy dendrimers bound
to the surface of Ad5 formed a synthetic polymer corona that greatly
altered various host interactions of Ad5 as well as
in vivo
distribution. The dendrimer corona (1) improved the ability of Ad5-derived
gene transfer vectors to transduce cells deficient for the primary
Ad5 cell membrane receptor and (2) modulated the binding of Ad5 to
blood coagulation factor X, one of the most critical virus–host
interactions in the bloodstream. It significantly enhanced the transduction
efficiency of Ad5 while also protecting it from neutralization by
natural antibodies and the complement system in human whole blood.
Ad5 with a synthetic dendrimer corona revealed profoundly altered
in vivo
distribution, improved transduction of heart, and
dampened vector sequestration by liver and spleen. We propose the
design of bioactive polymers that bind protein surfaces solely based
on their amphiphilic surface patches and protect against a naturally
occurring protein corona, which is highly attractive to improve Ad5-based
in vivo
gene therapy applications.
Patient-derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling of human diseases. They have heterogeneous morphologies with unclear biological causes and relationship to treatment response. Here, we use high-throughput, image-based profiling to quantify phenotypes of over 5 million individual colorectal cancer organoids after treatment with >500 small molecules. Integration of data using multi-omics modeling identifies axes of morphological variation across organoids: Organoid size is linked to IGF1 receptor signaling, and cystic vs. solid organoid architecture is associated with LGR5 + stemness. Treatment-induced organoid morphology reflects organoid viability, drug mechanism of action, and is biologically interpretable. Inhibition of MEK leads to cystic reorganization of organoids and increases expression of LGR5, while inhibition of mTOR induces IGF1 receptor signaling. In conclusion, we identify shared axes of variation for colorectal cancer organoid morphology, their underlying biological mechanisms, and pharmacological interventions with the ability to move organoids along them.
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