No abstract

Targeting organelles by modulating the redox potential of mitochondria is a promising approach to kill cancer cells that minimizes acquired drug resistance. However, it lacks selectivity because mitochondria perform essential functions for (almost) all cells. We show that enzyme-instructed self-assembly (EISA), a bioinspired molecular process, selectively generates the assemblies of redox modulators (e.g., triphenyl phosphinium (TPP)) in the pericellular space of cancer cells for uptake, which allows selectively targeting the mitochondria of cancer cells. The attachment of TPP to a pair of enantiomeric, phosphorylated tetrapeptides produces the precursors (L-1P or D-1P) that form oligomers. Upon dephosphorylation catalyzed by ectophosphatases (e.g., alkaline phosphatase (ALP)) overexpressed on cancer cells (e.g., Saos2), the oligomers self-assemble to form nanoscale assemblies only on the surface of the cancer cells. The cancer cells thus uptake these assemblies of TPP via endocytosis, mainly via a caveolae/raft-dependent pathway. Inside the cells, the assemblies of TPP-peptide conjugates escape from the lysosome, induce dysfunction of mitochondria to release cytochrome c, and result in cell death, while the controls (i.e., omitting TPP motif, inhibiting ALP, or removing phosphate trigger) hardly kill the Saos2 cells. Most importantly, the repeated stimulation of the cancers by the precursors, unexpectedly, sensitizes the cancer cells to the precursors. As the first example of the integration of subcellular targeting with cell targeting, this study validates the spatial control of the assemblies of nonspecific cytotoxic agents by EISA as a promising molecular process for selectively killing cancer cells without inducing acquired drug resistance.

A novel vaccine adjuvant based on a supramolecular hydrogel of a D-tetra-peptide is reported. Antigens can be easily incorporated into the hydrogel by a vortex or by gently shaking before injection. The vaccines can stimulate strong CD8+ T-cell responses, which significantly inhibits tumor growth. This novel adjuvant is expected to enable a wide range of sub-unit vaccines and help the production of antibodies.

Promising vaccine adjuvants of self‐assembling peptide hydrogels for protein ovalbumin (OVA) are introduced in this study. The hydrogels are formed by the enzyme of phosphatase, and the vaccine adjuvant potency of both l‐ and d‐peptide hydrogels is evaluated. The results indicate that, compared with the clinically used alum adjuvant, both l‐ and d‐peptide hydrogels can increase the IgG production of OVA for about 1.3 and 3.8 times, respectively. Both gels can enhance antigen uptake and induce dendritic cell maturation, and promote and prolong accumulation of antigen in lymph node, as well as evoke germinal center formation. However, the d‐peptide hydrogel with OVA exhibits a slightly more efficient accumulation of OVA in the lymph nodes and seems preventing tumor growth more significantly than its l‐counterpart. With the good biocompatibility and degradability of peptide hydrogels, the hydrogels described in this study have big potential for the production of protein vaccines for immunotherapy against different diseases.