Obesity, characterized by a body mass index (BMI) exceeding 30 kg/m2, is a significant public health concern affecting a considerable portion of the global population. The imbalance where energy intake surpasses energy expenditure leads to the deposition of excess energy primarily as triglycerides in the white adipose tissue (WAT). According to the data from the World Health Organization, overweight and obesity persist as the principal contributors to premature mortality globally [1]. Moreover, a substantial surge in overweight and obesity prevalence among children and adolescents has been documented [2,3]. By 2035, the global count of overweight or obese individuals may surpass 4 billion, up from over 2.6 billion in 2020, marking a surge from 38% to over 50% of the world's population by that same year [4]. Obesity-related conditions such as type II diabetes, cardiovascular disease, and fatty liver disease, significantly contribute to the societal and economic burdens [5,6]. Therefore, finding an effective anti-obesity treatment remains a significant challenge.

Current therapeutic options for obesity include dietary control, exercise, surgical procedures, and anti-obesity medications (AOMs). AOMs primarily function by targeting the central nervous system to suppress appetite, e.g., Orlistat, or the gastrointestinal tract to impede absorption, e.g., phentermine [7,8]. Recently, studies have focused on semaglutide and other glucagon-like peptide-1 (GLP-1) agonists as potential therapeutics for obesity. GLP-1 agonists are proven to stimulate insulin secretion and inhibit glucagon secretion, activating the central nervous system's GLP-1 receptor, which enhances satiety and diminishes food intake. Additionally, GLP-1 agonists stimulate the sympathetic nervous system, which reduces peripheral lipid accumulation and increases energy expenditure [9,10]. However, many AOMs are associated with severe adverse effects, including gastrointestinal complications, cardiovascular toxicity, headaches, and insomnia, while some AOMs have been found to be ineffective for weight reduction [11].

Adipose tissue, a specialized connective tissue primarily composed of adipocytes, can be subcategorized into three types: white, brown, and beige, each differing in structure, location, and function. The excessive accumulation and enlargement of adipocytes in white adipose tissues (WATs) is a significant pathological feature of obesity. The presence of fewer mitochondria in the cytoplasm of white adipocytes causes the storage of excess energy in the form of triglycerides [12]. In contrast, brown adipocytes contain a large number of multi-ridged mitochondria. Uncoupling protein 1 (UCP1) is highly expressed on the inner mitochondrial membrane of brown adipocytes, which eliminates the transmembrane proton concentration difference on both sides of the inner mitochondrial membrane, uncoupling the electron transfer and phosphorylation in the respiratory chain [13]. This process releases a significant amount of energy that would otherwise be used to produce ATP in the form of heat energy. Consequently, increasing the percentage of brown adipocytes leads to increased energy consumption and decreased lipid accumulation [14]. Therapeutic strategies that can increase the percentage of brown adipocytes and to increase energy consumption may benefit the anti-obesity treatment.

Interestingly, under appropriate stimulation, some white adipocytes were demonstrated to differentiate into brown adipocyte-like phenotypes, characterized by an upregulated level of UCP1 and multilocular lipid droplets [12]. These induced brown adipocyte-like cells are called beige adipocytes which constitute the majority of energy-dissipating cells and have drawn substantial attentions in AOM studies. Regarding mechanisms, the browning process of white adipocytes is critically influenced by adenosine 5′-monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptors (PPARs)-related pathways [15,16] . However, it is important to note that these pathways exist in various organs and participate in different physiological processes [17]. Therefore, a delivery system that targets adipocytes and selectively delivers browning agents may facilitate the browning process and improve the outcome of anti-obesity treatment. A peptide motif (CKGGRAKDC) was identified as a ligand for prohibitin, which is predominantly expressed in the vascular endothelial cells of WAT [18]. Nanoparticles modified with this peptide have been shown to effectively target WAT [19]. Furthermore, when administered intraperitoneally, nanomedicine based on polycations selectively targets visceral fat due to its high charge density [20]. Thereby, the combination of cationic nanoparticles and a localized drug delivery platform may further enhance the targeted delivery of browning agents towards adipocytes in WATs while achieving sustained and prolonged therapeutic effects in vivo.

In addition to AOMs, physical therapies including cold stimulation, hyperthermia, injection of deoxycholic acid have been explored to treat obesity systemically or locally [21], [22], [23]. Under cold stimulation, the body releases hormones such as norepinephrine, which act on β3-adrenergic receptors, and in turn activate UCP1, consuming a large amount of energy for thermogenesis thus reducing lipid accumulation [24,25]. As a treatment widely used in the anti-tumor therapies [26], [27], [28], local hyperthermia has also been found to remodel WAT by activating transient receptor potential vanilloid 1 (TRPV1) ion channels to promote browning and lipolysis, offering an alternative strategy for obesity treatment [29], [30], [31], [32].

Based on the above findings, we propose to develop an adipocyte targeted delivery of browning agents combined with localized photothermal therapy (PTT) for obesity treatment. Specifically, cationic albumin nanoparticles (cNPs) with adipocyte affinity/targetability are synthesized for targeted delivery of rosiglitazone (RSG) to white adipocytes to induce the browning process (Scheme 1). Next, an injectable Pluronic F127 hydrogel with thermosensitive gelation is used to create a subcutaneous reservoir for localized PTT with controlled and prolonged release of cNPs (Scheme 1). Due to its efficient sol-gel transition properties [33], cNPs loaded F127 gel precursor solution can be easily injected into the subcutaneous adipose tissues to achieve rapid in situ gelation. A single gel injection can support repeated local hyperthermia and achieve sustained release of cNPs targeting WATs. In addition, in vitro and in vivo studies were performed to validate the proposed therapeutic modality for the treatment of diet-induced obese (DIO) mice.