Immunoaffinity‐Mimetic Assembly of Peptide‐Aptamer Conjugates and Stem Cell‐Derived Exosomes into Hierarchical Microgels for Spinal Cord Injury Repair

Inspired by antibody‐antigen binding, this study develops an unprecedented immunoaffinity‐mimetic assembly strategy, with Peptide‐AptCD63 conjugates acting as antibody surrogates binding CD63 epitopes on mesenchymal stem cell‐derived exosomes. This creates a hierarchical microstructure intended to synergistically integrate antioxidative and anti‐inflammatory strategies with neuroregenerative processes to enhance spinal cord injury repair. ABSTRACT Mesenchymal stem cell‐derived exosomes (MSC‐Exo) containing various paracrine mediators have recently been recognized to promote functional recovery of spinal cord injury (SCI). However, their biomedical applications are hindered by limited possibilities for specific integration within the delivery systems. In this study, inspired by antibody‐antigen binding, we present an unprecedented assembly strategy that leverages immunoaffinity‐mimetic interactions of peptide‐aptamer (Peptide‐AptCD63) conjugates targeting CD63 markers on MSC‐Exo, yielding a hierarchical microstructure to enhance SCI repair. The conjugate, serving as the microgel scaffold, is synthesized by grafting azide‐modified AptCD63 onto poly(propargyl cysteine‐co‐γ‐propargyl‐L‐glutamate). It exhibits excellent antioxidant capability to mitigate oxidative stress and immune responses at the injury site. In addition, this conjugate constrains the tethered MSC‐Exo within the lesion site during administration, yet its nuclease susceptibility allows for the release of MSC‐Exo to promote the proliferation and migration of neural stem cells and to direct their differentiation into neurons rather than astrocytes. These synergistic effects ultimately enhance neuroregeneration, thereby promoting the motor function recovery of SCI mice. Our work represents a pioneering effort in harnessing the specificity of immunoaffinity‐mimetic interactions between aptamers and biomacromolecules for the high‐performance assembly of chemically vulnerable biologics, facilitating widespread applications across materials science and life science. Inspired by antibody-antigen binding, this study develops an unprecedented immunoaffinity-mimetic assembly strategy, with Peptide-Apt CD63 conjugates acting as antibody surrogates binding CD63 epitopes on mesenchymal stem cell-derived exosomes. This creates a hierarchical microstructure intended to synergistically integrate antioxidative and anti-inflammatory strategies with neuroregenerative processes to enhance spinal cord injury repair. ABSTRACT Mesenchymal stem cell-derived exosomes (MSC-Exo) containing various paracrine mediators have recently been recognized to promote functional recovery of spinal cord injury (SCI). However, their biomedical applications are hindered by limited possibilities for specific integration within the delivery systems. In this study, inspired by antibody-antigen binding, we present an unprecedented assembly strategy that leverages immunoaffinity-mimetic interactions of peptide-aptamer (Peptide-Apt CD63 ) conjugates targeting CD63 markers on MSC-Exo, yielding a hierarchical microstructure to enhance SCI repair. The conjugate, serving as the microgel scaffold, is synthesized by grafting azide-modified Apt CD63 onto poly(propargyl cysteine- co -γ-propargyl- L -glutamate). It exhibits excellent antioxidant capability to mitigate oxidative stress and immune responses at the injury site. In addition, this conjugate constrains the tethered MSC-Exo within the lesion site during administration, yet its nuclease susceptibility allows for the release of MSC-Exo to promote the proliferation and migration of neural stem cells and to direct their differentiation into neurons rather than astrocytes. These synergistic effects ultimately enhance neuroregeneration, thereby promoting the motor function recovery of SCI mice. Our work represents a pioneering effort in harnessing the specificity of immunoaffinity-mimetic interactions between aptamers and biomacromolecules for the high-performance assembly of chemically vulnerable biologics, facilitating widespread applications across materials science and life science. Advanced Science, EarlyView.