Abstract
Abstract Biologics have revolutionized the treatment of many diseases, particularly rare and genetic diseases, for which small-molecule drugs have shown limited efficacy, resulting in a surge in regulatory approvals over the past few decades. Despite these advances, biologic therapeutics face significant challenges, including complex formulation, manufacturing constraints, and safety and efficacy concerns following their administration. Issues with poor tissue penetration, reduced absorption across biological barriers, environmental and enzymatic degradation, and rapid clearance challenge efficacy, particularly at the target site, thereby increasing off-target exposure and the risk of adverse events. Biologic prodrugs offer a promising strategy to address these limitations by rendering biologics pharmacologically inactive until selectively activated in response to a defined physiological or pathological cue to confer bioactivity at the target site. This review discusses several biologic prodrugs and their activation mechanisms, including enzymatic and environmental triggers, such as pH changes, hypoxia, redox potential, and external stimuli (e.g. light). We explore various biologic prodrugs, including protein and recombinant fusion proteins, antibody-drug conjugates (ADCs), polymer-drug conjugates, and cell-penetrating peptides (CPPs) as masking motifs, as well as enzyme-prodrug therapy (EPT) systems, i.e. gene-directed enzyme prodrug therapy (GDEPT) and antibody-directed enzyme prodrug therapy (ADEPT). We also discuss lysosome-targeted biologic prodrugs that leverage the acidic, enzyme-rich, and compartmentalized lysosomal environment for controlled activation. Collectively, the examples discussed show biologic prodrugs as a versatile platform that selectively responds to physiological and environmental triggers, enabling enhanced spatial and temporal control of drug activation and thereby limiting systemic toxicity and other challenges associated with biologics. Graphical Abstract