Nutritional metal ions play critical roles in many important immune processes. Hence, effective modulation of metal ions may open up new forms of immunotherapy, termed as metalloimmunotherapy. Here, we demonstrate a prototype of cancer metalloimmunotherapy using cyclic dinucleotide (CDN) stimulator of interferon genes (STING) agonists and Mn 2+ . We screened various metal ions and discovered specific metal ions augmented STING agonist activity, wherein Mn 2+ promoted a 12- to 77-fold potentiation effect across the prevalent human STING haplotypes. Notably, Mn 2+ coordinated with CDN STING agonists to self-assemble into a nanoparticle (CDN-Mn 2+ particle, CMP) that effectively delivered STING agonists to immune cells. CMP administered either by local intratumoral or systemic intravenous injection initiated robust anti-tumor immunity, achieving remarkable therapeutic efficacy with minute doses of STING agonists in multiple murine tumor models. Overall, CMP offers a new platform for local and systemic cancer treatments, and this work underscores the great potential of coordination nanomedicine for metalloimmunotherapy.

Extradomain-B fibronectin (EDB-FN), one of the oncofetal fibronectin (onfFN) isoforms, is a high-molecular-weight glycoprotein that mediates cell adhesion and migration. The expression of EDB-FN is associated with a number of cancer-related biological processes such as tumorigenesis, angiogenesis, and epithelial-to-mesenchymal transition (EMT). Here, we report the development of a small peptide specific to EDB-FN for targeting prostate cancer. A cyclic nonapeptide, CTVRTSADC (ZD2), was identified using peptide phage display. A ZD2-Cy5 conjugate was synthesized to accomplish molecular imaging of prostate cancer in vitro and in vivo. ZD2-Cy5 demonstrated effective binding to up-regulated EDB-FN secreted by TGF-β-induced PC3 cancer cells following EMT. Following intravenous injections, the targeted fluorescent probe specifically bound to and delineated PC3-GFP prostate tumors in nude mice bearing the tumor xenografts. ZD2-Cy5 also showed stronger binding to human prostate tumor specimens with a higher Gleason score (GS9) compared to those with a lower score (GS 7), with no binding in benign prostatic hyperplasia (BPH). Thus, the ZD2 peptide is a promising strategy for molecular imaging and targeted therapy of prostate cancer.

COVID-19, which is caused by the emerging human coronavirus SARS-CoV-2, has become a global pandemic that poses a serious threat to human health. To date, no vaccines or specific antiviral drugs have been approved for the treatment of this disease in clinic. Herein, therapeutic antibodies for SARS-CoV-2 were obtained from hyperimmune equine plasma. First, a recombinant SARS-CoV-2 spike protein receptor-binding domain (RBD) was obtained in gram-level quantities through high-cell density fermentation of Chinese hamster ovary cells. Then, the binding of the RBD to the SARS-CoV-2 receptor, human angiotensin-converting enzyme 2, was verified by several biochemical methods. The efficacy of the RBD in triggering antibody response in vivo was subsequently tested in both mice and equines, and the results showed that the RBD triggered high-titer neutralizing antibody production in vivo. Immunoglobulin F(ab’) 2 fragments were prepared from equine antisera via removal of the Fc region from the immunoglobulins. Finally, a neutralization test with live virus demonstrated that RBD-specific F(ab’) 2 inhibited SARS-CoV-2 with an EC 50 of 0.07 μg/ml and an EC 80 of 0.18 μg/ml, showing a potent inhibitory effect on SARS-CoV-2. These results highlight RBD-specific equine immunoglobulin F(ab’) 2 fragment as a candidate for the treatment of SARS-CoV-2.