Dynamic Cell Factories for Feedback Regulated Expression of Therapeutic Proteins

The biomanufacturing of complex therapeutic proteins is often limited by endoplasmic reticulum (ER) stress and chronic activation of the unfolded protein response (UPR), which leads to apoptosis and reduced productivity. Traditional engineering strategiesrelying on constitutive modulationfrequently fail due to the emergence of secondary bottlenecks, disruption of endogenous homeostasis, and an inability to account for clonal variations or temporal fluctuations in cellular folding capacity over the course of a bioprocess. Here, we report the development of feedback-responsive cell factories that sense proteotoxic stress and dynamically modulate therapeutic transgene expression in real time, utilizing a closed-loop “sense-and-respond” architecture. We demonstrate that this approach mitigates ER stress and preserves cell viability without compromising overall protein production. This framework significantly enhanced the titers of two challenging therapeutic candidates: the bispecific antibody blinatumomab and tissue plasminogen activator (tPA). Our findings establish a proof-of-concept framework for the dynamic management of cellular stress, offering a valuable strategy that could be adapted to optimize the bioproduction of complex biologics.