Theragenerative Nanomaterials: Integrating Therapy, Regeneration, and Diagnosis-Navigating the Shared Pathways...

Nanotechnology convergence with regenerative medicine and oncology creates opportunities and challenges. Nanomaterials can be programmed to modulate biological responses, yet tissue repair and cancer share fundamental signaling pathways-including Wnt/β-catenin, Mitogen-Activated Protein Kinase (MAPK)/ Extracellular Signal-Regulated Kinase (ERK), Notch, and Hedgehog-raising a critical concern: pro-regenerative stimuli may inadvertently activate malignant programs. This review introduces the "theragenerative" paradigm, defined as nanomaterial platforms that concurrently integrate therapeutic (anti-cancer), regenerative (tissue repair), and diagnostic (real-time monitoring) functions. We examine the dual role of nanomaterials at the regenerative-oncology interface and propose context-aware platforms that dynamically balance healing and anti-tumor effects while minimizing oncogenic risk. Unlike conventional reviews that separately address nanocarriers for drug delivery or scaffolds for tissue engineering, this review is explicitly organized around the central question of how to establish safe boundaries between regenerative signals and tumor-promoting pathways-a distinction that defines the theragenerative framework.

We critically reviewed the literature on nanostructured scaffolds, cell-instructive surfaces, stimuli-responsive nanocarriers (pH, redox, enzyme, hypoxia), and biomimetic cell membrane-coated platforms, synthesizing findings from both foundational and recent studies. Studies on Extracellular Matrix (ECM) mimicry, tumor microenvironment-responsive drug delivery, and theragenerative systems were analyzed. Key shared pathways and translational challenges (safety, scalability, regulation, AI) were assessed.

Nanostructured scaffolds guide stem cell behavior and promote tissue repair by recreating ECM cues. Smart nanocarriers exploiting TME triggers (acidic pH, high glutathione, overexpressed Matrix Metalloproteinase (MMPs)) achieve precise drug delivery with reduced off-target effects. Theragenerative platforms combine therapy, regeneration, and diagnostics for real-time monitoring. However, the shared pathways-particularly Wnt/β-catenin, Notch, Hedgehog, and YAP/TAZ-pose a dual-edged risk: their activation promotes regeneration but may inadvertently drive malignant transformation, while their inhibition suppresses tumors but can impair tissue repair. This necessitates precise, context-dependent nanoparticle programming to navigate this therapeutic dilemma. Major hurdles include long-term genotoxicity, immunogenicity, manufacturing scalability, regulatory pathways for combination products, and AI-driven optimization.

Smart nanomaterials that sense their surroundings can operate at the crossroads of regenerative medicine and oncology. They either promote tissue repair or trigger tumor cell death while sparing healthy tissues. Successful clinical adoption requires a system that selectively modulates signaling pathways, restricts activity to defined sites, and controls timing precisely. This strategy could revolutionize personalized treatment for patients who simultaneously suffer from cancer and tissue defects.