Polyphenol-Scaffolded Modular Assembly of Heterotypic Cell-Cell Assemblies for Potentiating Cancer Immunotherapy

Cells existing in the form of clusters often exhibit distinct biological functions from their single-cell counterparts. However, the ability to modulate cell-cell interactions among multiple cell types through molecular scaffolds remains an ongoing challenge. Here, a supramolecular phenolic network on surfaces of live cells designed is engineered to act as modular scaffolds that promote intercellular interactions, presenting a universal platform for the construction of cell-cell assemblies (CCAs). Utilizing the inherent cell surface affinity of supramolecular phenolic network modules, a series of heterotypic CCAs is efficiently established by assembling five distinct microorganisms and five types of mammalian cells. A specific application of CCAs with the combination of L. casei and macrophages (L. casei@Mφ) is highlighted for enhanced cancer immunotherapy. Upon intravenous administration, L. casei@Mφ allows the chemotactic Mφ to facilitate the accumulation of L. casei at the tumor. The accumulated L. casei enables the polarization of tumor-associated Mφ toward a pro-inflammatory phenotype, markedly improving the immunotherapeutic response, slowing tumor progression, and mitigating lung metastasis. This work demonstrates the potential of polyphenol-scaffolded modular assembly in manipulating cell-cell interactions to enhance multicellular cooperation, offering a general approach to controlling complex cellular behaviors.