Objective:

To advance the translational development of macrophage-centered immunomodulatory therapies by linking nanodelivery design to macrophage biology and disease-relevant intracellular mechanisms, particularly through scavenger receptor-mediated targeting and cathepsin B-activated release.

Approach:

• Nanomedicine Overview: The review discusses the use of scavenger receptor-guided and cathepsin B-triggered nanodelivery systems to manipulate macrophage behavior by enhancing selective internalization and controlled drug release.
• Targeting Mechanisms: Scavenger receptors provide selective entry points in diseased macrophages, while cathepsin B acts as an endogenous trigger for drug release, facilitating targeted therapeutic effects.

Key Findings:

• Macrophages exhibit significant phenotypic plasticity influenced by microenvironmental signals, which can be targeted through nanomedicine.
• Scavenger receptors are enriched in pathological macrophages and play roles in lipid metabolism and inflammatory signaling, making them ideal targets for nanodelivery systems.
• Cathepsin B is elevated in pathological niches and serves as a trigger for controlled drug release from nanocarriers, enhancing therapeutic efficacy.

Interpretation:

The integration of receptor-mediated targeting and stimulus-responsive release mechanisms can enhance the effectiveness of macrophage-targeted therapies.

Limitations:

• Challenges include off-target sequestration, target heterogeneity, and ensuring functional bioavailability of nanocarriers, which may hinder effective treatment.

Conclusion:

The review emphasizes the need to align nanomedicine strategies with macrophage biology to improve therapeutic outcomes, focusing on the mechanisms of receptor-mediated targeting and stimulus-responsive release.