Intelligent nano delivery systems: Classification, stimuli-responsive mechanisms, and therapeutic applications in critical illnesses

Abstract

Critical illnesses such as sepsis and acute respiratory distress syndrome (ARDS) evolve rapidly and are dominated by systemic inflammatory dysregulation, oxidative stress, and abrupt microenvironmental remodeling, which collectively narrow the therapeutic window and amplify treatment-related toxicity. Conventional pharmacotherapy is often limited by non-selective biodistribution, insufficient lesion exposure, and dose-limiting adverse effects. Intelligent nano-delivery systems (INDS) address these barriers by coupling pathological cues (e.g., pH gradients, redox/ROS imbalance, and disease-associated enzymes) to defined carrier-state transitions, thereby enabling lesion-confined activation, controlled bioavailability, and, in selected designs, real-time readouts. In this review, we summarize the design logic of stimulus-responsive and targeting modules, and critically discuss how they translate endogenous signals into payload release or functional actuation in representative critical-illness settings. We further highlight emerging directions, including self-adaptive multi-input gating and biomimetic interfaces, and discuss key translational constraints (manufacturability, safety, and reproducibility) that must be addressed to advance INDS toward critical-care practice.