Delivery of Proteins and Nucleic Acids: Achievements and Challenges

I am delighted and honored to work with Ron and Vince on this Bioconjugate Chemistry special issue entitled “Delivery of Proteins and Nucleic Acids: Achievements and Challenges”. It has been almost 20 years since I first began work in this field as a bright-eyed postdoc. It was an exciting time; recombinant biologic drugs were being approved by the FDA, the human genome was sequenced, and RNA interference discovered. Soon after, I began my first academic position and while setting up my independent lab and mentoring my first students, the importance of therapeutic innovation hit home. My mother, Gail Sobaski, was diagnosed with stage IIIB diffuse large cell lymphoma. During her 18-month treatment regime, I witnessed first-hand how nonselective chemotherapies, radiation treatments, and bone marrow transplant can wreak havoc on the human body. While her treatments were ultimately successful and her cancer no longer detectable, she faced further life-threatening illness from treatment side effects including a depressed immune system. To combat this, the doctors administered filgrastim (a recombinant protein drug that stimulates white blood cell production) and eventually a new PEGylated variant that had just been FDA approved (pegfilgrastim), which promoted longer-term biological activity of the protein. Her immune system recovered, and since that time, she has remained in remission. In just under two decades, the field of biologics and nucleic acid drugs has witnessed many ups and downs. The field is now experiencing a renaissance, where biologic drugs have a higher FDA approval rate than small molecules. Moreover, several cell and gene therapies have now been FDA approved, with many more in the pipeline yielding promising clinical results to save lives. I recently had the pleasure of meeting the first pediatric CAR-T cell therapy recipient in the US, Emily Whitehead, and her parents, Kari and Tom. Emily’s life was saved by a lentiviral gene therapy that engineered her immune cells to expresses a chimeric T cell receptor that selectively destroyed her relapsed lymphoblastic leukemia. Her family and the Emily Whitehead Foundation are now dedicated to obtaining funding and increasing awareness for innovative treatments that are less toxic and more targeted. These and many other personal experiences have continued to humanize the power of therapeutic innovation to decrease side effects and improve treatment efficacy. In this special issue, we move a step closer to this goal by highlighting a series of innovative synthetic systems that show many promising attributes for safe, affordable, scalable, stable, and effective biologic and nucleic acid therapeutic advancement. As Ron and Vince point out below, getting large biomolecules through the cellular barrier is not an easy task. As highlighted herein, many innovative delivery approaches are described involving use of synthetic conjugates, polymer carriers, peptides, and scaffolds with responsive chemistry to overcome the many biological barriers that exist. While many clinical successes have paved the way, including FDA approval of the first nonviral siRNA drug, several hurdles remain. The high level of cross-disciplinary collaboration exemplified by this field will ultimately enable more synthetic bioconjugates to reach their final goal: to improve and prolong quality of life for patients and their families.