Synthetic hydrogels have been extensively investigated as artifi cial extracellular
matrices (ECMs) for tissue engineering in vitro and in vivo. Crucial
challenges for such hydrogels are sustaining long-term cytocompatible encapsulation
and providing appropriate cues at the right place and time for spatiotemporal
control of the cells. Here, in situ supramolecularly assembled and
modularly modifi ed hydrogels for long-term engineered mesenchymal stem
cell (eMSC) therapy are reported using cucurbit[6]uril-conjugated hyaluronic
acid (CB[6]-HA), diaminohexane conjugated HA (DAH-HA), and drug-conjugated
CB[6] (drug-CB[6]). The eMSCs producing enhanced green fl uorescence
protein (EGFP) remain alive and emit the fl uorescence within CB[6]/DAH-HA
hydrogels in mice for more than 60 d. Furthermore, the long-term expression
of mutant interleukin-12 (IL-12M) by eMSCs within the supramolecular
hydrogels results in effective inhibition of tumor growth with a signifi cantly
enhanced survival rate. Taken together, these fi ndings confi rm the feasibility
of supramolecular HA hydrogels as 3D artifi cial ECMs for cell therapies and
tissue engineering applications.