Enzyme‐Responsive Delivery of Multiple Proteins with Spatiotemporal Control

Abstract

The growth of tissues and organs is regulated by orchestrated signals from biomolecules such as enzymes and growth factors. The ability to deliver signal molecules in response to particular biological events (e.g., enzyme expression and activation) holds great promise towards tissue healing and regeneration. The current delivery vehicles mainly rely on hydrolysable scaffolds and thin films of protein-containing polymers, which cannot be programmed to respond to biological signals. We report herein an injectable delivery platform based on enantiomeric protein nanocapsules, which can deliver multiple proteins with spatiotemporal control in response to the tissue proteases secreted during wound healing. Exemplified by stroke and diabetic wound healing in mice, sequential delivery of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) greatly enhances tissue revascularization and vessel maturation, providing effective delivery vehicles for tissue engineering and reparative medicine.

Systematic optimization of an engineered hydrogel allows for selective control of human neural stem cell survival and differentiation after transplantation in the stroke brain

“…Cell-loaded hydrogels provide structural support that not only directly promote the survival of encapsulated cells [6], but also promote cell infiltration from the surrounding parenchyma [7] and reduce the glial scar and inflammation at the ischemic border [8, 9]. Similarly, local drug delivery from injectable hydrogels can achieve sustained [3, 10, 11] or sequential delivery [12] in a time- and space-controlled manner, while enhancing protein stability, diffusion distance and in vivo bioactivity [11]. Polymer-based hydrogels are highly customizable as their composition can be modified to adapt to the host tissue.…”

Cell-Demanded VEGF Release via Nanocapsules Elicits Different Receptor Activation Dynamics and Enhanced Angiogenesis

“…The D -chiral enantiomer has lower degradation kinetics compared to the L -chiral peptide 15,18 ; thus, n(VEGF) synthesized with an increasing D -chiral peptide content will have a slower degradation rate, and thereby a slower release rate of VEGF. 33 The selection of this plasmin-sensitive peptide sequence as the crosslinker is such that VEGF can be released when proteolytic and fibrinolytic proteases are present from endothelial cells (Fig. 1b).…”

“…The release rate from nanocapsules in this damaged environment can be inferred in a similar study, where we demonstrated 100 ng of n(Protein) 100% was mostly released by day 3 and 100 ng of n(Protein) 25% was mostly released from day 3 to day 6. 33 …”

“…33 By introducing peptides as crosslinkers to the polymer shell, cell-demanded release of the protein is realized via the catalytic hydrolysis of peptides by proteases in the extracellular matrices. Herein, we utilize these VEGF nanocapsules to study the molecular and cellular differences between a sustained delivery and a bolus delivery.…”

Hydrogels for brain repair after stroke: an emerging treatment option

“…VEGF was encapsulated within protease-labile, water-soluble nanocapsules formed through radical polymerization of acrylate-modified peptides (release rate is controlled through mixing L and D crosslinking peptides). We demonstrated that controlled release in vivo is associated with improved vascularization within the stroke peri-infarct and infarct regions [41]. …”