A responsive hydrogel delivers RNA therapy to diabetic wounds, reducing tissue breakdown and inflammation by releasing treatment in sync with the wound’s chemical signals.
(Nanowerk Spotlight) A small cut on the foot should not be life altering. But for people living with diabetes, that cut can turn into a wound that refuses to close, defies treatment, and worsens until amputation becomes unavoidable. This is not uncommon. Chronic wounds affect millions of people, and in diabetes, the body’s ability to repair itself becomes so disrupted that even minor injuries can become critical.
The problem lies deep within the biology of wound healing. In a diabetic wound, chemical signals become imbalanced. The area becomes flooded with reactive oxygen molecules that damage tissue and prolong inflammation. Enzymes that would normally help clear debris instead begin to break down the very structures needed for recovery. One of these enzymes, matrix metalloproteinase 9, becomes overactive. Rather than supporting healing, it prevents the rebuilding of the tissue scaffold by degrading collagen and other essential components.
Treatments have tried to interrupt this cycle using antioxidant ointments, anti-inflammatory drugs, and gene-targeting therapies. But each of these has run into the same obstacle. The wound environment is chemically unstable and biologically aggressive. It breaks down most drugs before they can act.
One promising approach is the use of small interfering RNA (siRNA), a molecule that can switch off harmful genes with high precision. However, RNA is delicate. It degrades quickly, struggles to reach target cells, and often fails to stay active long enough to have a therapeutic effect.
More importantly, it responds to the chemical state of the wound itself. When oxidative stress rises, the material changes its structure and begins releasing its genetic cargo. When conditions improve, it slows down. This creates a system that not only delivers treatment but does so with timing and sensitivity tuned to the biology of the wound. The result is a coordinated and localized therapy that offers new possibilities for treating wounds that resist healing.
Microenvironment-programmed siRNA-based hydrogel for spatiotemporal gene silencing in wound healing. (Image: reprinted with permission by Wiley-VCH Verlag) (click on image to enlarge)
The study presents a system that combines precise gene silencing with a hydrogel responsive to oxidative conditions. At its core is a molecule known as SS HPT. This is a positively charged polymer with a branched structure, designed to carry small interfering RNA that targets the gene encoding matrix metalloproteinase 9. The polymer protects the RNA from degradation and facilitates its delivery into cells, where the internal chemical environment triggers the release of the RNA by breaking the polymer apart.
To deliver this system directly to the wound site, the researchers embedded the RNA-loaded SS HPT particles into a hydrogel made from hyaluronic acid. This is a naturally occurring material used widely in medicine because it is biocompatible, water retaining, and supports tissue regeneration. The hydrogel is engineered to respond to reactive oxygen species, which are elevated in diabetic wounds. It contains two molecular components, one derived from β cyclodextrin and the other from ferrocene. These components form a network that is stable under normal conditions but begins to disassemble in the presence of oxidative stress, triggering the release of the RNA therapy.
To fine tune the behavior of the hydrogel, the researchers used molecular simulations to study how different concentrations of the two reactive components affected the structure and release profile. They found that a ten percent incorporation of each component provided the optimal balance. This version of the hydrogel remained intact in low stress environments but released its RNA cargo rapidly when exposed to oxidative conditions.
In physical tests, the hydrogel retained its shape under normal conditions but softened and broke down when exposed to hydrogen peroxide, a common source of reactive oxygen in wounds.
In cell studies, the RNA delivery system proved both efficient and safe. The particles entered cells readily and released their RNA payload, significantly reducing the production of MMP 9. Importantly, the delivery system showed low toxicity across a range of concentrations and performed better than a commonly used gene delivery polymer in both effectiveness and safety.
The researchers then tested the system in a diabetic wound model in mice. They created full thickness skin wounds and treated them with either saline, the RNA complex alone, the hydrogel alone, or the complete RNA-loaded hydrogel system. Over ten days, the group treated with the complete system showed the fastest and most complete healing. The wound area reduced by over 96 percent, significantly better than any of the comparison groups.
Tissue analysis revealed that the treated wounds had lower levels of MMP 9, better organized collagen, and a higher ratio of type I to type III collagen. Type I collagen is a key indicator of high quality healing. The wounds also showed better epithelial coverage and reduced inflammatory damage. The treatment did not increase unwanted cell growth or abnormal tissue formation, which suggests that it supports healing without triggering side effects commonly associated with growth-promoting therapies.
Further experiments examined how the treatment affected the immune environment of the wound. Using imaging techniques and molecular markers, the researchers showed that the treatment reduced levels of reactive oxygen species and shifted immune cells from a pro-inflammatory state to a regenerative one. Specifically, there was a decrease in M1 macrophages, which drive inflammation, and an increase in M2 macrophages, which promote tissue repair.
To explore the broader biological impact of the treatment, the researchers analyzed gene expression in the wound tissue. They found that the treatment reduced the activity of genes involved in inflammation, collagen breakdown, and oxidative stress. At the same time, it increased the expression of genes involved in collagen formation and tissue regeneration. These changes support the idea that the treatment not only protects tissue from damage but also creates a more favorable environment for healing.
Safety testing showed that the hydrogel and its components did not damage major organs and had no measurable toxic effects on blood cells. The material remained localized at the wound site and did not trigger systemic responses.
The findings offer a promising approach to one of the most stubborn problems in wound care. By using a material that responds directly to the wound environment, the therapy is able to deliver treatment in a more coordinated and adaptive way. The gene silencing mechanism provides specificity, while the hydrogel ensures the therapy is released only when needed. This kind of responsiveness is important in complex conditions like diabetic wounds, where timing and location are critical to successful healing.
While the system has not yet been tested in humans, and questions remain about long term safety and large scale production, the study provides a clear framework for how to design therapies that work with, rather than against, the body’s own healing signals.
The combination of material science and gene regulation demonstrated in this work could lead to new treatment options not only for diabetic wounds but also for other conditions where chronic inflammation and tissue breakdown play a role.
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ORCID information
Fu-Jian Xu (Beijing University of Chemical Technology)
, 0000-0002-1838-8811 corresponding author
Yang Li (Beijing University of Chemical Technology)
, 0000-0002-6493-3972 corresponding author
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