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Spatiotemporally Engineered Protein Delivery via Integrated Covalent Coupling and Pathological Triggers for Precision

Rui Quan^1,2, Xianglin Hou¹, Jing Zhang^3,4

¹Laboratory of Integrative Physiology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.

Advanced Materials (Deerfield Beach, Fla.)

|September 22, 2025

Summary

This study introduces a biomaterial platform for precise, enzyme-triggered drug delivery to injured tissues. Sequential delivery of regenerative factors and immunomodulators significantly improved spinal cord injury and cardiac repair outcomes.

Keywords:

biomaterials injury repair responsive release

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Area of Science:

Biomaterials Science
Regenerative Medicine
Tissue Engineering

Background:

Tissue injury creates a dynamic microenvironment that current therapies struggle to modulate effectively.
A need exists for precision interventions that respond to and control pathological changes over time.

Purpose of the Study:

To develop a biomaterial platform for spatiotemporally controlled delivery of therapeutic factors.
To leverage endogenous enzyme triggers for sequential release of regenerative and immunomodulatory agents.

Main Methods:

Utilized Sortase A (SrtA)-mediated covalent conjugation for precise factor attachment.
Developed enzyme-responsive hyaluronic acid gel (T-HA) for controlled release.
Investigated sequential delivery of CNTF/FGF2 followed by IL-4 in spinal cord injury (SCI) models.
Assessed FGF2 delivery preceding IL-4 in myocardial infarction (MI) models.

Main Results:

Sequential delivery (CNTF/FGF2 then IL-4) significantly enhanced SCI recovery compared to reverse order.
FGF2 delivery before IL-4 resulted in superior cardiac functional restoration post-MI.
The system demonstrated effective modulation of the therapeutic window for inflammation and remodeling.

Conclusions:

The developed biomaterial platform enables precise, sequential delivery of therapeutics based on endogenous injury signals.
This approach optimizes treatment timing, enhancing recovery in complex tissue injury models.
Offers a versatile strategy for managing dynamic pathological processes in injured tissues.