Immune-Phase-Aware Protein Delivery via Polymeric Nanomedicines for Tissue Regeneration: A Review

Abstract

Immune regulation governs tissue regeneration through coordinated time-dependent interactions among innate and adaptive immune cells. Although protein therapeutics such as cytokines and growth factors offer high specificity, their clinical translation is limited by rapid degradation and, more critically, mismatches between delivery profiles and dynamic immune states. Polymeric nanomedicines address these challenges by integrating protein stabilization with programmable, microenvironment-responsive release. Through enzyme-, redox-, and pH-sensitive chemistries, these systems can be engineered to couple protein availability to selected inflammatory cues while also shaping nanoimmune interactions, cellular uptake, and signaling duration. This Review links polymer design to multicellular immune-phase dynamics that include neutrophils, macrophage subsets, antigen-presenting cells, T cells, regulatory T cells, natural killer cells, and group 2 innate lymphoid cells. We distinguish phase-permissive, phase-biased, phase-synchronized, and phase-adaptive delivery strategies using operational evidence criteria rather than release kinetics alone. We further discuss tissue-specific design constraints, protein corona variability, immunotoxicity, manufacturing, and regulatory translation. Together, these considerations position polymeric nanomedicines as immune-aware therapeutic interfaces, whose success depends on delivering biologically interpretable protein signals at the appropriate phase of repair.