A Navigation Constitution for Autonomous Nanocarriers Crossing Biological Barriers under Uncertainty, Off-Target Risk, and Human Oversight

Nanocarriers designed to alter their behavior in response to biological conditions create a safety problem that extends beyond conventional formulation quality and passive targeting. Their sensed inputs may influence transport, surface exposure, cellular entry, intracellular trafficking, or payload release, allowing uncertainty at one stage to propagate into later and potentially irreversible actions. This Original Governance and Control Theory Article proposes a navigation constitution for organizing such condition-dependent behavior without assuming cognition, unrestricted agency, or validated autonomous performance. The architecture separates sensing, barrier-state estimation, uncertainty assessment, authorization, material action, consequence verification, logging, and human intervention. It establishes distinct permissions for observation, route adaptation, and drug release; contracts the permitted action set when evidence is uncertain or contradictory; and gives prohibited-state signals priority over therapeutic mission signals. Biological-barrier recognition is treated as a probabilistic and revisable estimate because biodistribution, protein-corona evolution, cellular uptake, and intracellular release can vary across compartments and contexts. Traceability requirements connect formulation identity, observed cues, inferred states, authorized actions, deviations, and consequences, while intervention rights preserve human authority to stop, redesign, or withdraw a system. Preclinical evaluation is organized around nominal, ambiguous, conflicting, off-target, failure, and rescue scenarios. Manufacturing assessment must determine whether scale-up and lot variation preserve conditional behavior rather than only conventional particle attributes. The proposed constitution is an original conceptual synthesis requiring product-specific computational, experimental, manufacturing, and translational validation. It does not establish clinical safety, regulatory acceptance, universal applicability, or deployment readiness.