The use of the edible photosynthetic cyanobacterium *Arthrospira platensis* (spirulina) as a biomanufacturing platform has been limited by a lack of genetic tools. Here we report genetic engineering methods for stable, high-level expression of bioactive proteins in spirulina, including large-scale, indoor cultivation and downstream processing methods. Following targeted integration of exogenous genes into the spirulina chromosome (chr), encoded protein biopharmaceuticals can represent as much as 15% of total biomass, require no purification before oral delivery and are stable without refrigeration and protected during gastric transit when encapsulated within dry spirulina. Oral delivery of a spirulina-expressed antibody targeting *campylobacter*—a major cause of infant mortality in the developing world—prevents disease in mice, and a phase 1 clinical trial demonstrated safety for human administration. Spirulina provides an advantageous system for the manufacture of orally delivered therapeutic proteins by combining the safety of a food-based production host with the accessible genetic manipulation and high productivity of microbial platforms.

Benjamin W. Jester, Hui Zhao, Mesfin Gewe, Thomas Adame, Lisa Perruzza, David T. Bolick, Jan Agosti, Nhi Khuong, Rolf Kuestner, Caitlin Gamble, Kendra Cruickshank, Jeremy Ferrara, Rachelle Lim, Troy Paddock, Colin Brady, Stacey Ertel, Miaohua Zhang, Alex Pollock, Jamie Lee, Jian Xiong, Michael Tasch, Tracy Saveria, David Doughty, Jacob Marshall, Damian Carrieri, Lauren Goetsch, Jason Dang, Nathaniel Sanjaya, David Fletcher, Anissa Martinez, Bryce Kadis, Kristjan Sigmar, Esha Afreen, Tammy Nguyen, Amanda Randolph, Alexandria Taber, Ashley Krzeszowski, Brittney Robinett, David B. Volkin, Fabio Grassi, Richard Guerrant, Ryo Takeuchi, Brian Finrow, Craig Behnke, James Roberts