Macrophage reprogramming through scavenger receptor-guided and cathepsin B-triggered nanodelivery: from intracellular mechanisms to translational applications.

Macrophages are highly plastic innate immune cells. Their functional states are dynamically shaped by inflammatory signals, metabolic stress, and disease-associated remodeling. In cancer and atherosclerosis, pathological macrophages contribute to immune suppression, plaque destabilization, and therapeutic resistance, making their reprogramming a critical translational goal. Recent advances in nanomedicine provide new opportunities to manipulate macrophage behavior by combining selective cellular entry with conditionally controlled intracellular release. This review focuses on scavenger receptor-guided and cathepsin B-triggered nanodelivery systems as a mechanism-aligned strategy for phenotypic remodeling. While scavenger receptors provide selective molecular gateways enriched in diseased macrophage populations, cathepsin B serves as an endogenous trigger for subsequent nanocarrier disassembly and payload release. We discuss how aligning targeted internalization and enzymatic release can reshape macrophage function. We also examine how these platforms engage intracellular vulnerability networks, highlighting signal transducer and activator of transcription 3 (STAT3) as a translationally relevant node that stabilizes pathological states rather than an exclusive mechanistic axis. Finally, we assess major translational challenges, including off-target sequestration, target heterogeneity, and functional bioavailability. This review aims to advance the translational development of macrophage-centered immunomodulatory therapies by linking nanodelivery design to macrophage biology and disease-relevant intracellular mechanisms.