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Over the past few decades, various therapies that block TGF-β signaling have been studied in preclinical and clinical trials; however, due to the dual systemic effects of TGF-β and the complexity of the tumor microenvironment, the results of clinical trials have been disappointing. Smart nanodelivery systems with the ability to respond to stimuli and target specific sites address the Janus-faced biology of TGF-β through spatially precise inhibition.Nanoparticles targeting TGF-β can form a positive feedback loop, enhancing their penetration and delivery efficiency, thanks to the role of TGF-β in remodeling the tumor microenvironment. This review first provides an overview of the functions of TGF-β signaling, summarizes various tools for inhibiting TGF-β signaling, and comprehensively highlights advanced nanoparticles targeting TGF-β. It elucidates the symbiotic interaction between TGF-β blockade and nanoparticles, where nanomaterial-based strategies optimize the specificity of TGF-β targeting, and TGF-β blockade in turn enhances the efficiency of nanoparticle-mediated delivery. Additionally, current challenges and future directions are emphasized to guide the future development of TGF-β blockade strategies and anti-tumor therapeutic nanoparticles.
Summary
In recent years, nanotechnology targeting the TGF-β signaling pathway has emerged as a promising approach for cancer treatment. TGF-β plays a dual role in tumors: it suppresses tumors early but promotes growth, metastasis, and immune suppression in advanced stages. Traditional TGF-β inhibitors face challenges like systemic side effects, off-target effects, and poor tumor penetration. Smart nanoparticle delivery systems offer a revolutionary solution by precisely targeting tumors, reducing damage to normal tissues, and remodeling the tumor microenvironment (e.g., loosening the extracellular matrix, improving vascular function, and reactivating immune cells). This creates a virtuous cycle: nanoparticles inhibit TGF-β to enhance drug penetration, while improved therapy further boosts anti-tumor effects.
The review covers various TGF-β-targeting nanoparticle strategies, including stimuli-responsive polymer nanoparticles, theranostic inorganic/hybrid nanoparticles, and biomimetic cell membrane-coated nanoparticles. These can synergize with chemotherapy, immunotherapy, or targeted therapy—e.g., a "two-wave" strategy where TGF-β inhibitor-loaded nanoparticles first remodel the microenvironment, followed by a second wave of therapeutic nanoparticles to significantly improve efficacy. However, challenges remain, such as certain inorganic materials accidentally activating TGF-β and promoting metastasis, underscoring the need for material safety. Future efforts should focus on developing next-generation nanoparticles that intelligently distinguish tumor stages and responsively adapt to the microenvironment, key for clinical translation.
References:
DOI: 10.7150/thno.126517
