Researchers created a targeted fat loss therapy using light-sensitive nanoparticles that activate fat-burning processes inside adipocytes, offering a new direction for localized obesity treatment without systemic drugs.
(Nanowerk Spotlight) Obesity treatment is undergoing a pharmaceutical shift. Medications like semaglutide (Ozempic, Wegovy), tirzepatide (Mounjaro, Zepbound), and liraglutide (Saxenda) have redefined clinical expectations for weight loss by targeting the hormonal pathways that regulate appetite and glucose metabolism. These drugs act as mimics of incretin hormones such as GLP-1 and GIP, which slow gastric emptying, reduce hunger, and improve insulin sensitivity. Clinical trials have reported double-digit percentage reductions in body weight, prompting widespread adoption and reshaping the public conversation around obesity management.
But the enthusiasm comes with caveats. These treatments require ongoing, often indefinite, administration to maintain weight loss. Discontinuation typically leads to weight regain. Side effects are common and include nausea, vomiting, gastrointestinal discomfort, and muscle mass reduction.
Moreover, these drugs primarily suppress appetite rather than directly influencing the underlying cellular biology of fat storage. They do not alter how fat cells (adipocytes), which store energy as lipids, regulate fat accumulation, nor do they reverse the structural and metabolic changes that occur in obese fat tissue.
Fat cells are not passive reservoirs of excess energy. They actively protect their lipid stores from degradation by enclosing them in protein-coated droplets. One of the key regulators of access to these stores is chaperone-mediated autophagy (CMA), a selective process in which cells break down specific proteins inside lysosomes, specialized compartments responsible for digesting and recycling cellular material.
In adipocytes, CMA governs the breakdown of proteins such as perilipin 2 (PLIN2), a protein that coats fat droplets and prevents enzymes from breaking them down. Removing PLIN2 allows enzymes like adipose triglyceride lipase (ATGL) to initiate fat breakdown, or lipolysis. Experimental models have shown that blocking PLIN2 or activating CMA systemically can reduce fat mass in animals on high-fat diets.
Despite these findings, practical ways to activate CMA in a controlled, cell-specific manner remain limited. Systemic chemical inducers lack selectivity and may trigger off-target effects in non-adipose tissues. Genetic methods are not feasible for therapeutic use. Mild thermal stress can activate CMA by upregulating heat shock proteins like HSC70, but there are few techniques that deliver such stress precisely and only to the desired cells.
Advances in nanotechnology offer a new approach. Materials can now be designed to respond to external cues such as light or temperature, and to home in on specific cell types by mimicking their surface properties. In cancer therapy, photothermal nanoparticles have already demonstrated the ability to deliver drugs and heat locally with spatial precision. The application of similar strategies to adipose tissue, particularly for regulating intracellular pathways like CMA, remains largely unexplored.
Embedded in a biodegradable hydrogel for local retention, the material allows precise activation of CMA—and therefore lipolysis—only in the treated tissue. This design enables external control over fat metabolism at the cellular level without relying on systemic appetite suppression or invasive procedures.
The central component of the system is a nanoparticle designed to perform multiple tasks: deliver a drug payload, respond to light, and target adipocytes specifically. Its core is made of polydopamine, a material known for its strong absorption of near-infrared (NIR) light and ability to convert that energy into localized heat. Polydopamine also degrades under acidic conditions, such as those found inside lysosomes, which facilitates intracellular drug release.
Encapsulated within this core is rosiglitazone, a compound previously studied for its metabolic effects in adipose tissue. Although rosiglitazone is best known as a PPARγ agonist with insulin-sensitizing properties, it also increases the expression of adipose triglyceride lipase (ATGL), a key enzyme responsible for initiating lipolysis. At high systemic doses, rosiglitazone can promote weight loss in mice, but its clinical use has been limited by concerns over cardiovascular risk and fluid retention. By embedding it in a targeted, localized delivery system, the current study avoids systemic exposure while preserving its beneficial effect on lipid metabolism.
To direct the nanoparticle specifically to fat cells, the surface is coated with membranes extracted from mature adipocytes. This membrane coating retains key surface proteins involved in homotypic recognition—adhesion molecules that enable adipocytes to preferentially interact with each other. This design takes advantage of the natural tendency of fat cells to engage in self-recognition, increasing the likelihood that the nanoparticles will be internalized by adipocytes rather than other cells in the surrounding tissue.
These nanoparticles are then embedded in a hydrogel formed from hyaluronic acid crosslinked with tyramine. The hydrogel acts as a local depot that retains the nanoparticles at the injection site and releases them gradually over several days. This design allows for repeated activation through NIR light without the need for re-injection. The hydrogel is biodegradable and responds to hyaluronidase enzymes naturally present in tissue, enabling controlled breakdown and release over time.
Construction of ARNP-H and proposed CMA-mediated anti-obesity mechanism. A) Adipocyte membranes were isolated from adipocytes and used to coat the surfaces of RNP. The resulting ARNP was proposed for facilitating uptake by adipocytes over other cells in adipose tissue. B) A schematic illustration depicts the mechanism of ARNP-H treatment for a CMA-mediated anti-obesity effect. ARNP was embedded in a hydrogel to enhance retention at the local injection site. ARNP was selectively taken up by adipocytes, providing NIR-responsive heat stress specifically to these cells. Upon NIR irradiation, the mild heat stress upregulated HSC70, which then co-localized with PLIN2 and facilitated its lysosomal trafficking. Consequently, the degradation of PLIN2, which served as a protective barrier for lipid droplets, allowed cytosolic ATGL to access the lipid droplets and promoted lipolysis. (Reprinted from DOI:10.1002/adma.202418445, CC BY-NC-ND 4.0) (click on image to enlarge)
The combined system—adipocyte membrane-coated, rosiglitazone-loaded, polydopamine nanoparticle in hydrogel—is referred to as ARNP-H. It is administered subcutaneously into white adipose tissue, where it remains localized and inactive until activated by NIR light.
Upon NIR exposure, the polydopamine core generates heat, raising the temperature of surrounding adipocytes to approximately 42 degrees Celsius. This level of mild thermal stress is sufficient to increase the expression of heat shock cognate protein 70 (HSC70), a chaperone protein essential for CMA. HSC70 recognizes proteins bearing the CMA targeting motif and facilitates their translocation to lysosomes, where they are degraded.
One of these targets is perilipin 2 (PLIN2), a structural protein that coats lipid droplets and restricts access by lipases. When PLIN2 is degraded via CMA, ATGL can associate with the lipid droplet surface and initiate triglyceride breakdown. In this study, colocalization of HSC70 and PLIN2, followed by their trafficking to lysosomes, was observed in adipocytes treated with ARNP-H and exposed to NIR light. This process did not occur in control groups lacking the membrane coating, the drug payload, or the NIR activation.
Further experiments confirmed that the effect was both specific and reversible. PLIN2 levels declined after NIR activation and returned to baseline within 24 hours, indicating that CMA activation was transient and dependent on stimulation. ATGL expression increased in response to rosiglitazone, and its colocalization with lipid droplets was enhanced following PLIN2 degradation. The result was a measurable reduction in lipid content within treated adipocytes.
In mouse models fed a high-fat diet, the system produced significant reductions in body weight and fat mass over a five-week period. Animals received weekly subcutaneous injections of ARNP-H into inguinal white adipose tissue, followed by NIR irradiation on three consecutive days per week. Imaging confirmed that the hydrogel retained the nanoparticles at the injection site for at least nine days. Temperature measurements showed a reliable increase in local tissue temperature upon NIR exposure, with no comparable effect in control animals.
Body composition analysis using micro-computed tomography showed a decrease in both subcutaneous and visceral fat volumes in treated animals. Histological examination revealed smaller adipocytes, reduced lipid droplet size, and lower triglyceride content in fat tissue. Importantly, these effects were not accompanied by reductions in food intake, suggesting that the weight loss was driven by enhanced lipolysis rather than changes in feeding behavior.
No significant changes were observed in markers of liver or kidney toxicity, and inflammatory cytokine levels in adipose tissue remained stable. The proportion of tumor necrosis factor alpha (TNFα)-expressing macrophages did not increase with treatment, indicating minimal immune activation. Plasma adiponectin levels rose in treated animals, a finding consistent with improved metabolic function.
Mechanistic validation included experiments using leupeptin, a lysosomal protease inhibitor. In these animals, PLIN2 accumulated in lysosomes rather than being degraded, confirming that the system relies on lysosomal proteolysis via CMA. Western blot analysis further demonstrated increased levels of HSC70 and ATGL and decreased levels of PLIN2 in treated tissue following NIR exposure. These molecular changes correlated with the physiological observations of fat loss and tissue remodeling.
Compared to earlier phototherapy approaches that rely on inducing cell death or oxidative stress, this system operates at lower temperatures and engages a regulated intracellular pathway. Rather than destroying adipocytes, it reprograms them to degrade their own lipid stores. The combination of light-responsiveness, membrane targeting, and controlled drug release offers a degree of precision that has not been available in previous metabolic interventions.
By using endogenous cell machinery to trigger lipolysis, the system avoids the drawbacks of appetite suppression or systemic hormone manipulation. It also offers a modular platform: the membrane coating could be adapted to other cell types, and the drug payload could be replaced to target different intracellular pathways. These features suggest broader applicability in conditions marked by autophagy dysfunction, including metabolic syndrome, neurodegeneration, and certain age-related diseases.
While further studies are needed to determine long-term safety, dosing strategies, and translational potential in humans, the findings here establish a proof of concept for externally controlled activation of selective protein degradation pathways in targeted cell populations. In doing so, they open a path toward more precise, cell-intrinsic strategies for managing complex diseases like obesity.
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