Key Takeaways & Executive Findings
- •• • Covalent functionalization achieves up to 85% drug loading efficiency and enables controlled release kinetics, reducing burst release to <15% in 24 hours, which is critical for maintaining therapeutic windows and minimizing systemic toxicity. • • Heteroatom doping (e.g., nitrogen, sulfur) increases the specific surface area to 1200–2000 m²/g and enhances electrical conductivity by 3–5 orders of magnitude, improving biosensor sensitivity to detect biomarkers at concentrations as low as 1 pM. • • Non-covalent assembly with PEG or peptides improves physiological dispersibility by >90% and extends blood circulation half-life from minutes to >12 hours, addressing a key bottleneck in in vivo drug delivery. • • Surface-engineered CNMs demonstrate antibacterial efficacy of >99.9% against both Gram-positive and Gram-negative bacteria at concentrations below 50 µg/mL, offering a potential alternative to conventional antibiotics in wound healing applications.
Abstract
Carbon nanomaterials (CNMs), including carbon nanotubes, graphene, and fullerenes, exhibit exceptional promise in precision biomedicine due to their tunable biocompatibility, programmable surface chemistry, large specific surface area, and quantum confinement effects. However, their clinical translation is hindered by aggregation, poor physiological dispersibility, and limited targeting specificity. This review systematically elaborates on surface engineering strategies—covalent functionalization, non-covalent assembly, and heteroatom doping—to optimize the multifunctionality, biocompatibility, and targeting capabilities of CNMs at the nano-bio interface. We explore how engineered interfaces enable advanced applications in biosensing, stimuli-responsive drug delivery, multimodal bioimaging, antibacterial therapy, and regenerative tissue engineering. The review also addresses challenges such as scalability, long-term toxicity, and regulatory hurdles, and proposes future directions to expedite clinical adoption. By providing a comprehensive framework for rational surface design, this work aims to bridge the gap between fundamental materials science and clinical needs, offering a roadmap for developing next-generation carbon-based theranostics.
1. Introduction
Conventional biomedical materials, such as polymeric nanoparticles and liposomes, suffer from insufficient targeting specificity, poor physiological stability, and suboptimal therapeutic indices. In oncology, for instance, systemic chemotherapy remains limited by off-target toxicity and multidrug resistance, while in tissue engineering, existing scaffolds often fail to recapitulate the mechanical and biochemical cues of native extracellular matrix. These shortcomings underscore an urgent need for materials that combine high surface area, tunable surface chemistry, and intrinsic conductivity—properties that carbon nanomaterials (CNMs) uniquely offer.
Despite their promise, CNMs have not yet achieved widespread clinical adoption. Aggregation in physiological media, rapid clearance by the reticuloendothelial system, and nonspecific biodistribution have historically curtailed their performance. This review addresses these bottlenecks by systematically analyzing surface engineering strategies—covalent functionalization, non-covalent assembly, and heteroatom doping—that precisely modulate the nano-bio interface. By linking these modifications to specific biomedical applications, we provide a rational design framework that enhances dispersibility, targeting, and therapeutic efficacy, thereby accelerating the translation of CNMs from bench to bedside.
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YANG Mengyao, LUAN Yujuan, SONG Haoyang, PENG Mengke, DU Juan, JI Youan, HOU Senlin, CHEN Aibing, YOON Juyoung (2026). Surface Engineering-Guided Functional Design of Carbon Nanomaterials for Precision Biomedicine. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-026-4295-5
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Frequently Asked Questions
What are the primary failure mechanisms of carbon nanomaterials in physiological environments, and how does surface engineering mitigate them?
The primary failure mechanisms include aggregation due to hydrophobic interactions, opsonization leading to rapid macrophage uptake, and enzymatic degradation. Surface engineering mitigates these by introducing hydrophilic moieties (e.g., PEG) that sterically stabilize the particles, reducing protein corona formation and extending circulation half-life from minutes to >12 hours. Additionally, covalent functionalization with targeting ligands (e.g., antibodies, peptides) enhances specific cellular uptake, as evidenced by a 3-fold increase in tumor accumulation in preclinical models.
How do heteroatom doping strategies improve the electrochemical performance of carbon nanomaterials for biosensing applications?
Heteroatom doping (e.g., nitrogen, sulfur) modulates the electronic structure of carbon nanomaterials, increasing the density of active sites and charge-carrier mobility. This results in a 3–5 order of magnitude increase in electrical conductivity and a lower detection limit of 1 pM for biomarkers such as dopamine or glucose. For example, nitrogen-doped graphene electrodes exhibit a sensitivity of 0.5 µA/µM and a linear range of 0.1–100 µM, which is critical for early disease diagnosis.
What are the scalability challenges in producing surface-engineered carbon nanomaterials for clinical translation, and what cost-effective methods exist?
Scalability challenges include batch-to-batch reproducibility, high production costs, and complex purification steps. Covalent functionalization often requires expensive reagents and multi-step reactions, while non-covalent assembly may suffer from weak binding stability. However, recent advances in continuous-flow microreactors and green chemistry approaches have reduced production costs by up to 40% and improved yield to >90%. For instance, plasma-assisted functionalization enables solvent-free, one-step modification, making large-scale production more feasible.
How do surface-engineered carbon nanomaterials achieve targeted drug delivery, and what are the release kinetics under physiological conditions?
Targeting is achieved by conjugating ligands that recognize overexpressed receptors on diseased cells (e.g., folate, transferrin). Drug release is often triggered by pH, redox potential, or enzymatic activity in the tumor microenvironment. For example, doxorubicin-loaded graphene oxide functionalized with folic acid shows a cumulative release of 70% within 48 hours at pH 5.0, compared to only 20% at pH 7.4, enabling site-specific chemotherapy with reduced systemic toxicity.
What are the long-term toxicity and biocompatibility profiles of surface-engineered carbon nanomaterials, and how do they compare to conventional materials?
Long-term toxicity depends on surface chemistry, dose, and route of administration. PEGylated carbon nanotubes have shown no significant acute toxicity in mice at doses up to 10 mg/kg, with clearance via renal and hepatobiliary pathways. However, chronic exposure may induce granuloma formation in the liver. Compared to conventional materials like liposomes, surface-engineered CNMs exhibit higher stability and lower immunogenicity when properly coated, but require rigorous long-term studies to establish safety margins.
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