Current clinical management of obesity relies primarily on glucagon-like peptide-1 (GLP-1) receptor agonists or peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists. However, GLP-1 agonists often lead to weight regain after discontinuation, while PPAR-γ agonist efficacy is limited by the pro-inflammatory adipose microenvironment. Here, we report an adipose-targeted nanocomposite microneedle patch (LRSG-SG@MN) for obesity treatment via an immuno-metabolic modulation strategy based on the co-delivery of rosiglitazone and semaglutide. This platform leverages the intrinsic affinity of nano-lipid droplets for adipocytes to deliver rosiglitazone, thereby activating PPAR-γ signaling and initiating mitochondrial biogenesis. Concurrently, the sustained release of semaglutide reprograms the local immune microenvironment by driving macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotypes. Mechanistically, this resolution of adipose inflammation alleviates the suppression of thermogenesis, creating a circuit that potentiates the browning effects of rosiglitazone. In high-fat diet-induced obese mice, this strategy demonstrated robust efficacy, significantly reducing adiposity and ameliorating glucolipid metabolic disorders. Notably, the system exhibited excellent weight maintenance capacity following treatment cessation without significant rebound, achieving efficient and durable anti-obesity outcomes. This study unveils the non-central immunomodulatory function of semaglutide and establishes an adipose-targeted, long-acting nanocomposite microneedle platform that achieves combined therapeutic outcomes through adipose tissue inflammatory reprogramming coupled with browning induction, offering a novel strategy for sustainable obesity management.

Hybrid-phase metal-organic frameworks (MOFs) are a class of intriguing heterostructures for diverse applications, the properties of which are governed by their chemical composition, framework topology, and morphology. Herein, we report the structural and morphological evolution of flexible MOFs induced by the lattice change of template during heteroepitaxial growth. We demonstrate that the epitaxially grown flexible Fe-MOFs can be varied from one structure to another to adapt to the lattice of the template Zr-MOFs. Thus, flexible Fe-MOFs with similar chemical compositions and topology can be epitaxially grown on different Zr-MOFs over huge lattice constant gradient. We also demonstrate that the morphology of the heterostructures is affected by the degree of lattice difference between the template MOFs and the epitaxial MOFs. The reported results could pave the way toward the rational design of hybrid-phase MOFs guided by the principles of reticular chemistry.

A novel self-delivered prodrug system was fabricated for tumor-targeting therapy. In this nanosystem, the Arg-Gly-Asp-Ser (RGDS) tetrapeptide was used to improve the therapeutic index to integrin-overexpressing tumor cells. The antitumorous drug camptothecin was further appended to the ε-amino group of lysine by 20-O-succinyl linkage and controllably released via hydrolytic cleavage. Prodrug molecules self-assembled into fibrillar nano-architectures and achieved the capability of self-delivery after being injected subcutaneously into mice. Introduction of hydrophobic myristic acid favored the self-assembly and enhanced the cellular internalization of the prodrugs. In vitro and in vivo studies demonstrated that the self-assembled nanofibers could effectively target integrinoverexpressing tumorous cells and inhibit tumor growth via RGD-mediated specific targeting. Therefore, the traditional idea that fibrillar structures hold low therapeutic efficacy due to poor cell uptake can be challenged.

A mesoporous silica/gold (MSN/Au) nanocomposite was designed for photo-controlled drug delivery targeted specifically at tumor cells. The MSN/Au nanocomposite was composed of MSN-based drug carriers and gold nanoparticle (AuNP)-based indicators. While the MSN-based drug carrier was a mesoporous silica nanoparticle immobilized with photo-switchable azobenzene (Azo) moieties, the AuNP-based indicator was a fluorescence-quenched AuNP modified with a matrix metalloproteinase (MMP) substrate and poly(ethylene glycol). The two kinds of nanoparticles were connected by an α, β cyclodextrin (α, β CD) dimer "bridge." In vitro studies demonstrated that the nanocomposite specifically interacted with tumor sites overexpressing MMP-2, which enabled guidance of the subsequent UV light irradiation for releasing entrapped drugs. Through integration of the AuNP-based indicator and the MSN-based drug carrier, the MSN/Au nanocomposite could precisely localize the released drug to tumor sites, thereby significantly improving therapeutic efficacy.