Human immune and gut microbial parameters associated with inter-individual variations in COVID-19 mRNA vaccine-induced immunity.

COVID-19 mRNA vaccines induce protective adaptive immunity against SARS-CoV-2 in most individuals, but there is wide variation in levels of vaccine-induced antibody and T-cell responses. However, the mechanisms underlying this inter-individual variation remain unclear. Here, using a systems biology approach based on multi-omics analyses of human blood and stool samples, we identified several factors that are associated with COVID-19 vaccine-induced adaptive immune responses. BNT162b2-induced T cell response is positively associated with late monocyte responses and inversely associated with baseline mRNA expression of activation protein 1 (AP-1) transcription factors. Interestingly, the gut microbial fucose/rhamnose degradation pathway is positively correlated with mRNA expression of AP-1, as well as a gene encoding an enzyme producing prostaglandin E2 (PGE2), which promotes AP-1 expression, and inversely correlated with BNT162b2-induced T-cell responses. These results suggest that baseline AP-1 expression, which is affected by commensal microbial activity, is a negative correlate of BNT162b2-induced T-cell responses.

Lipid-Raft-Targeted Molecular Self-Assembly Inactivates YAP to Treat Ovarian Cancer.

The Yes-associated protein (YAP) is a major oncoprotein responsible for cell proliferation control. YAP's oncogenic activity is regulated by both the Hippo kinase cascade and uniquely by a mechanical-force-induced actin remodeling process. Inspired by reports that ovarian cancer cells specifically accumulate the phosphatase protein ALPP on lipid rafts that physically link to actin cytoskeleton, we developed a molecular self-assembly (MSA) technology that selectively halts cancer cell proliferation by inactivating YAP. We designed a ruthenium-complex-peptide precursor molecule that, upon cleavage of phosphate groups, undergoes self-assembly to form nanostructures specifically on lipid rafts of ovarian cancer cells. The MSAs exert potent, cancer-cell-specific antiproliferative effects in multiple cancer cell lines and in mouse xenograft tumor models. Our work illustrates how basic biochemical insights can be exploited as the basis for a nanobiointerface fabrication technology which links nanoscale protein activities at specific subcellular locations to molecular biological activities to suppress cancer cell proliferation.

Integrin and Heparan Sulfate Dual-Targeting Peptide Assembly Suppresses Cancer Metastasis.

Metastasis is one of the ongoing challenges in cancer therapy which most treatments failed to address. Inspired by the upregulated expression of both integrin ß1 and heparan sulfate in metastatic tumors, we developed an integrin/HS dual-targeting peptide assembly that selectively inhibits cancer cell migration and invasion. Particularly, the dual-targeting peptide self-assembles into nanofibrous microdomains specifically on the cancer cell membrane, triggering spatial organization of integrins, which form clusters on the apical membrane. Via the actin cytoskeleton that physically connects to integrin clusters, the oncogene yes-associated protein, which regulates cancer metastasis, is deactivated. We showed that in multiple cancer cell lines, including the highly metastatic pancreatic cancer cells, the dual-targeting peptide exerts potent and dose-dependent antimetastatic effects. Our work illustrates how basic biochemical insights can be exploited as the basis for nano-biointerface fabrication, which is potentially a general design strategy for nanomedicine development.

Regulating Higher-Order Organization through the Synergy of Two Self-Sorted Assemblies.

The extracellular matrix (ECM) is the natural fibrous scaffold that regulates cell behavior in a hierarchical manner. By mimicking the dynamic and reciprocal interactions between ECM and cells, higher-order molecular self-assembly (SA), mediated through the dynamic growth of scaffold-like nanostructures assembled by different molecular components, was developed. Designed and synthesized were two self-sorted coumarin-based gelators, a peptide molecule and a benzoate molecule, which self-assemble into nanofibers and nanobelts, respectively, with different dynamic profiles. Upon the dynamic growth of the fibrous scaffold assembled from peptide gelators, nanobelts assembled from benzoate gelators transform into a layer-by-layer nanosheet, reaching ninefold increase in height. By using light and an enzyme, the spatial-temporal growth of the scaffold can be modified, leading to in situ height regulation of the higher-order architecture.