Chitosan Nanoparticles in GelMA Hydrogel Deliver Resveratrol in pH-Responsive Manner In Vitro

Researchers have built a two-part delivery system that releases the plant compound resveratrol more quickly in acidic surroundings and more slowly at neutral pH, and they report that the resveratrol it delivers dampened oxidative, inflammatory, and apoptosis-associated signals in lab-grown neural and microglial cells. The work, published as an open-access research article in BMC Biotechnology, is explicitly an in vitro proof of concept rather than a demonstration of any treatment effect in living animals or patients.

The platform combines two materials. First, resveratrol-loaded chitosan-based nanoparticles, designated RSV@PCCC, were formed by electrostatic self-assembly, a process in which oppositely charged components drive spontaneous particle formation. The team characterized the physicochemical properties of the particles, measured how resveratrol escaped from each formulation under different pH conditions, and then tested the resveratrol-containing materials on cells stimulated with lipopolysaccharide, a standard inflammatory trigger.

The pH sensitivity of the nanoparticles showed up clearly in the release measurements. At pH 7.2, close to physiological neutrality, the optimized particles maintained relatively stable hydrodynamic characteristics and released resveratrol gradually, with cumulative release reaching about 50 percent after 72 hours. When the surrounding environment was made acidic at pH 6.4, cumulative release climbed to roughly 74 percent over the same period.

Embedding the nanoparticles in the GelMA hydrogel slowed the release further, an effect the researchers interpret as sustained delivery. From the hydrogel formulation, cumulative resveratrol release was approximately 58 percent at pH 6.4 and about 36 percent at pH 7.2 after 72 hours. In other words, the hydrogel acted as a secondary diffusion barrier, extending the release timeline compared with the free nanoparticles while retaining the same pH-responsive pattern.

The cellular experiments focused on responses relevant to secondary injury after acute brain injury, a process the authors describe as involving interconnected oxidative, inflammatory, and apoptosis-associated cellular changes. Resveratrol itself has known antioxidant and anti-inflammatory activities, but its limited stability in water and rapid clearance from the body restrict how long it stays biologically active, which is the practical problem the delivery platform is meant to address.

In lipopolysaccharide-stimulated neural and microglial cells, the resveratrol-containing formulations reduced intracellular reactive oxygen species, a marker of oxidative stress. The anti-inflammatory effect was quantified at the protein level: RSV@PCCC reduced expression of the inflammatory signaling proteins interleukin-1 beta and tumor necrosis factor alpha by approximately 60 percent and 50 percent, respectively, in the tested cells.

The formulations also shifted a key balance in the apoptosis-associated pathway. The ratio of Bax, a pro-apoptotic protein, to Bcl-2, an anti-apoptotic one, fell by roughly 50 percent with RSV@PCCC and by about 40 percent with the hydrogel formulation, RSV@PCCC-Hydrogel. Taken together, the authors report attenuation of oxidative stress, inflammatory activation, and apoptosis-associated changes under the tested in vitro conditions.

The authors are careful about scope. Their conclusions state that the chitosan-based nanoparticle and GelMA platform enabled pH-responsive and sustained resveratrol release and attenuated the lipopolysaccharide-induced cellular changes, and that these findings provide an in vitro proof of concept for modulating cellular processes associated with secondary injury after acute brain injury. They position the platform for further evaluation in physiologically relevant models of acute brain injury, which would be needed before any claims about therapeutic benefit could be considered.

Several limitations follow directly from the study design. All cellular findings come from cells in culture stimulated with a single inflammatory trigger, not from brain tissue or animal models, so the results describe associations between resveratrol exposure and measured markers rather than effects on injury outcomes. Release behavior was measured over 72 hours in buffer conditions, and the acidic pH used in the release tests is a model condition rather than a direct measurement of any injury environment. The article was shared early as a peer-reviewed accepted manuscript carrying a permanent DOI, a citable version that will be replaced by the final Version of Record.

Within those boundaries, the study adds a concrete data point to the broader effort to improve resveratrol delivery. By pairing a pH-sensitive nanoparticle with a hydrogel depot, the researchers obtained both environmental responsiveness and prolonged release in a single formulation, along with measurable reductions in three classes of injury-relevant cellular markers in vitro. Whether the same pH-triggered release and cellular effects hold up in tissue-level models of acute brain injury remains the explicit next step the authors identify.

Subject of Research: A pH-responsive resveratrol delivery platform of chitosan nanoparticles embedded in GelMA hydrogel, evaluated in vitro in neural and microglial cells

Article Title: pH-responsive resveratrol delivery using chitosan-based nanoparticles embedded in GelMA: in vitro evaluation of acute brain injury-relevant cellular responses

Article References: Chen, Z., Cao, W., Zhao, M., Wang, Q., Li, Y., Fu, R., Gao, X., Ke, Z., Xu, X., & Li, S. (2026). pH-responsive resveratrol delivery using chitosan-based nanoparticles embedded in GelMA: in vitro evaluation of acute brain injury-relevant cellular responses. BMC Biotechnology. https://doi.org/10.1186/s12896-026-01225-y

Image Credits: AI Generated

DOI: 10.1186/s12896-026-01225-y

Keywords: resveratrol, chitosan nanoparticles, GelMA hydrogel, pH-responsive drug delivery, acute brain injury, oxidative stress, neuroinflammation, microglial cells, apoptosis, controlled release, in vitro study, drug delivery