The design of materials for regenerative medicine has focused on delivery of small molecule drugs, proteins, and cells to help accelerate healing. Additionally, biomaterials have been designed with covalently attached mimics of growth factors, cytokines, or key extracellular matrix components allowing the biomaterial itself to drive biological response. While the approach may vary, the goal of biomaterial design has often centered on promoting either cellular infiltration, degradation, vascularization, or innervation of the scaffold. Numerous successful studies have utilized this complex, multicomponent approach; however, we demonstrate here that a simple nanofibrous peptide hydrogel unexpectedly and innately promotes all of these regenerative responses when subcutaneously implanted into the dorsal tissue of healthy rats. Despite containing no small molecule drugs, cells, proteins or protein mimics, the innate response to this material results in rapid cellular infiltration, production of a wide range of cytokines and growth factors by the infiltrating cells, and remodeling of the synthetic material to a natural collagen-containing ECM. During the remodeling process, a strong angiogenic response and an unprecedented degree of innervation is observed. Collectively, this simple peptide-based material provides an ideal foundational system for a variety of bioregenerative approaches.

Background Senescent cells accumulate in tissues over time as part of the natural ageing process and the removal of senescent cells has shown promise for alleviating many different age-related diseases in mice. Cancer is an age-associated disease and there are numerous mechanisms driving cellular senescence in cancer that can be detrimental to recovery. Thus, it would be beneficial to develop a senolytic that acts not only on ageing cells but also senescent cancer cells to prevent cancer recurrence or progression. Methods We used molecular modelling to develop a series of rationally designed peptides to mimic and target FOXO4 disrupting the FOXO4-TP53 interaction and releasing TP53 to induce apoptosis. We then tested these peptides as senolytic agents for the elimination of senescent cells both in cell culture and in vivo. Findings Here we show that these peptides can act as senolytics for eliminating senescent human cancer cells both in cell culture and in orthotopic mouse models. We then further characterized one peptide, ES2, showing that it disrupts FOXO4-TP53 foci, activates TP53 mediated apoptosis and preferentially binds FOXO4 compared to TP53. Next, we show that intratumoural delivery of ES2 plus a BRAF inhibitor results in a significant increase in apoptosis and a survival advantage in mouse models of melanoma. Finally, we show that repeated systemic delivery of ES2 to older mice results in reduced senescent cell numbers in the liver with minimal toxicity. Interpretation Taken together, our results reveal that peptides can be generated to specifically target and eliminate FOXO4+ senescent cancer cells, which has implications for eradicating residual disease and as a combination therapy for frontline treatment of cancer. Funding This work was supported by the Cancer Early Detection Advanced Research Center at Oregon Health & Science University.

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