RESUMO
While proteolysis-targeting chimeras (PROTACs) hold great potential for persistently reprogramming the immunosuppressive tumor microenvironment via targeted protein degradation, precisely activating them in tumor tissues and preventing uncontrolled proteolysis at off-target sites remain challenging. Herein, a light-triggered PROTAC nanoassembly (LPN) for photodynamic indoleamine 2,3-dioxygenase (IDO) proteolysis is reported. The LPN is derived from the self-assembly of prodrug conjugates, which comprise a PROTAC, cathepsin B-specific cleavable peptide linker, and photosensitizer, without any additional carrier materials. In colon tumor models, intravenously injected LPNs initially silence the activity of PROTACs and accumulate significantly in targeted tumor tissues due to an enhanced permeability and retention effect. Subsequently, the cancer biomarker cathepsin B begins to trigger the release of active PROTACs from the LPNs through enzymatic cleavage of the linkers. Upon light irradiation, tumor cells undergo immunogenic cell death induced by photodynamic therapy to promote the activation of effector T cells, while the continuous IDO degradation of PROTAC simultaneously blocks tryptophan metabolite-regulated regulatory-T-cell-mediated immunosuppression. Such LPN-mediated combinatorial photodynamic IDO proteolysis effectively inhibits tumor growth, metastasis, and recurrence. Collectively, this study presents a promising nanomedicine, designed to synergize PROTACs with other immunotherapeutic modalities, for more effective and safer cancer immunotherapy.
RESUMO
While mesalamine, a 5-aminosalicylic acid (5-ASA), is pivotal in the management of inflammatory bowel disease (IBD) through both step-up and top-down approaches in clinical settings, its widespread utilization is limited by low bioavailability at the desired site of action due to rapid and extensive absorption in the upper gastrointestinal (GI) tract. Addressing mesalamine's pharmacokinetic challenges, here, we introduce nanoassemblies composed exclusively of a mesalamine prodrug that pairs 5-ASA with a mucoadhesive and cathepsin B-cleavable peptide. In an IBD model, orally administered nanoassemblies demonstrate enhanced accumulation and sustained retention in the GI tract due to their mucoadhesive properties and the epithelial enhanced permeability and retention (eEPR) effect. This retention enables the efficient uptake by intestinal pro-inflammatory macrophages expressing high cathepsin B, triggering a burst release of the 5-ASA. This cascade fosters the polarization toward an M2 macrophage phenotype, diminishes inflammatory responses, and simultaneously facilitates the delivery of active agents to adjacent epithelial cells. Therefore, the nanoassemblies show outstanding therapeutic efficacy in inhibiting local inflammation and contribute to suppressing systemic inflammation by restoring damaged intestinal barriers. Collectively, this study highlights the promising role of the prodrug nanoassemblies in enhancing targeted drug delivery, potentially broadening the use of mesalamine in managing IBD.
Assuntos
Doenças Inflamatórias Intestinais , Macrófagos , Mesalamina , Pró-Fármacos , Mesalamina/química , Mesalamina/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Animais , Camundongos , Humanos , Nanopartículas/química , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/administração & dosagemRESUMO
Extracellular matrix (ECM) undergoes dynamic inflation that dynamically changes ligand nanospacing but has not been explored. Here we utilize ECM-mimicking photocontrolled supramolecular ligand-tunable Azo+ self-assembly composed of azobenzene derivatives (Azo+) stacked via cation-π interactions and stabilized with RGD ligand-bearing poly(acrylic acid). Near-infrared-upconverted-ultraviolet light induces cis-Azo+-mediated inflation that suppresses cation-π interactions, thereby inflating liganded self-assembly. This inflation increases nanospacing of "closely nanospaced" ligands from 1.8 nm to 2.6 nm and the surface area of liganded self-assembly that facilitate stem cell adhesion, mechanosensing, and differentiation both in vitro and in vivo, including the release of loaded molecules by destabilizing water bridges and hydrogen bonds between the Azo+ molecules and loaded molecules. Conversely, visible light induces trans-Azo+ formation that facilitates cation-π interactions, thereby deflating self-assembly with "closely nanospaced" ligands that inhibits stem cell adhesion, mechanosensing, and differentiation. In stark contrast, when ligand nanospacing increases from 8.7 nm to 12.2 nm via the inflation of self-assembly, the surface area of "distantly nanospaced" ligands increases, thereby suppressing stem cell adhesion, mechanosensing, and differentiation. Long-term in vivo stability of self-assembly via real-time tracking and upconversion are verified. This tuning of ligand nanospacing can unravel dynamic ligand-cell interactions for stem cell-regulated tissue regeneration.
RESUMO
Most supramolecular systems were discovered by using a trial-and-error approach, leading to numerous synthetic efforts to obtain optimal supramolecular building blocks for selective guest encapsulation. Here, we report a simple coassembly strategy for preparing tamoxifen-selective supramolecular nanomaterials in an aqueous solution. The synthetic amphiphile molecule, 1,1,2,2-tetraphenylethylene (TPE), promotes large tamoxifen aggregate disassembly into smaller, discrete aggregates such as ribbon-like and micellar assemblies in coassembled solutions, enhancing the solubility and dispersion. The TPE moiety exhibits enhanced emission upon tamoxifen interaction, enabling the observation of the coassembled species in an aqueous solution for cell imaging. The tamoxifen-selective fluorescent micelles in the presence of a 1:1 molar ratio of TPE derivative with tamoxifen show enhanced tamoxifen absorption and anticancer effects against MCF-7 breast cancer cells. These supramolecular approaches, based on the coassembly of building blocks with molecular structural similarity, can provide a novel strategy for the efficient development of selective molecular carriers with enhanced biological activities.