Engineering design of platelet-mimicking therapeutic systems: multilevel biomimicry, gating strategies, and translational boundaries

Platelet-mimicking therapeutic systems have expanded well beyond hemostasis, yet clinical translation is increasingly constrained by controllability and safety-bounded deployability rather than proof-of-function. Here, we propose an engineering framework that maps design choices onto four coupled layers-structure, membrane, function, and gating-to decouple efficacy from systemic thrombotic and immunological risks. Central to this framework is a minimal platelet interface (MPI), defined as a bounded, low-gain basal state in circulation that permits lesion engagement while resisting systemic amplification. We render this interface measurable through membrane critical quality attributes (CQAs) (QC-linked membrane features), including receptor retention/orientation, shear-capture thresholds under flow, and baseline procoagulant leakage in the OFF state. We further elevate gating from simple stimulus triggering to permission-based gating (stimulus is necessary but not sufficient) by requiring risk-stratified logic, predefined activation thresholds and dynamic ranges, and validated deactivation or fail-safe constraints under worst-case conditions such as high shear and systemic inflammation. Finally, we organize applications along a risk gradient-execution for hemostasis and reversal, navigation for vascular inflammation and ischemia-reperfusion, and multilayer-gated de-risking for cancer and infection-explicitly linking biomimetic design to falsifiable safety boundaries, release criteria, chemistry, manufacturing, and controls (CMC), and regulatory requirements.