Graphene-Based Materials: A Multifunctional Platform for Comprehensive Perioperative Management of Cancer

Abstract

Perioperative cancer care constitutes a continuous management process that spans from precise preoperative diagnosis and surgical resection to long-term recurrence monitoring after surgery, each stage of which presents distinct challenges and critically influences patient prognosis and quality of life. Current independent technologies, often coupled with single-functional materials, are unable to cope with this complex, multi-stage, continuous trajectory, resulting in fragmented improvements that are frequently offset by disease deterioration or recurrence. Graphene-based materials (GBMs), owing to their unique physicochemical properties, intrinsic bioactivities, programmable architectures, and dynamic responsiveness, hold promise for constructing a novel multifunctional integrated platform capable of synergistically tackling the multifaceted challenges across the perioperative continuum. Unlike previous literature that focused on isolated applications, this study is the first to conceptualize GBMs as a unified platform for perioperative cancer closed-loop management, covering preoperative diagnosis and intraoperative navigation, postoperative rehabilitation (including hemostasis, antibacterial defense, and wound healing), tissue regeneration, long-term recurrence monitoring, and intervention. Our objective is to illustrate how GBM-based platforms integrate disparate stages of care, thereby transforming perioperative cancer management from a passive, fragmented approach into a proactive and closed-loop system that enables dynamic monitoring, intelligent responsiveness, and precise intervention throughout the entire treatment cycle. Despite these advantages, clinical translation still necessitates advances in biosafety profiling, renal clearance evaluation, and regulatory pathway navigation, which can be achieved through rational material design, standardized safety assessment, and early engagement with regulatory agencies. Such efforts will facilitate the transition of GBMs from the laboratory to the clinic and ultimately improve patient outcomes and quality of life.

Introduction

The traditional perioperative period of cancer care encompasses a continuous clinical pathway that extends from initial surgical decision-making to postoperative recovery,^1,2 a trajectory that profoundly determines long-term oncological prognosis and patient survival.^3,4 Despite significant advances, complex cancer surgeries continue to encounter persistent challenges, including inaccurate tumor delineation, incomplete resection,^5,6 uncontrollable hemorrhage,^7,8 and infection-impaired wound healing.⁹ Beyond these immediate perioperative hurdles, cancer surgery presents two frequently overlooked long-term issues including functional tissue regeneration and the need for prolonged surveillance of metastatic recurrence.^10–12

Critically, these challenges are biologically interconnected. The accuracy of preoperative diagnosis and intraoperative navigation technology jointly determines the degree of tumor radicality.^13,14 The thoroughness of resection not only affects the probability of postoperative complications such as bleeding, inflammation, and delayed healing, but also directly determines the extent of residual lesions.¹⁵ Moreover, the surgery-induced adverse microenvironment, such as inflammation, can weaken tissue regenerative capacity and significantly increase the risk of residual tumor cell recurrence.^16,17 Therefore, tumor postoperative monitoring needs to extend over several months or even years, a duration far longer than that required for most benign surgical diseases. When residual or metastatic lesions are detected during monitoring, precise interventions such as chemotherapy, targeted therapy, or immunotherapy are required.^18,19 Within the closed-loop process, it is necessary to clarify the concepts of several different stages. Traditional perioperative care comprises preoperative diagnosis and tumor margin mapping, intraoperative navigation, and early postoperative hemostasis, anti-infection, and wound healing (ie, short-term postoperative rehabilitation).²⁰ Notably, postoperative rehabilitation itself is a component of traditional perioperative care and serves as the starting point of postoperative recovery. On this basis, given the long-term risk of recurrence in post-surgical tumor patients, and the fact that tissue regeneration and functional recovery often require months or even years to complete, this review further expands the scope of the cancer perioperative period to encompass long-term postoperative care, including tissue regeneration and functional recovery, long-term recurrence monitoring, and precise intervention. Among them, long-term monitoring refers to continuously tracking signs of recurrence using methods such as liquid biopsy. Recurrence intervention is defined as active treatment initiated after abnormal findings are detected, including clearance of cancer stem cells, remodeling of the tumor microenvironment, and vaccine carrier-based therapy. If necessary, the cycle can revert to the surgical stage to complete the closed loop. Given these multifaceted aspects, this review adopts a broader perspective, defining “perioperative cancer management” as a continuous spectrum that extends from preoperative diagnosis to functional tissue recovery and long-term recurrence monitoring and intervention (Figure 1A).

Figure 1.

Schematic diagram of closed-loop management of cancer perioperative period and multifunctional properties of graphene-based materials (GBMs) with extended definition. (A) An extended definition of cancer perioperative closed-loop management. The traditional perioperative period (solid box) includes preoperative diagnosis, intraoperative navigation, and early postoperative rehabilitation. The extended section (dashed box) covers tissue regeneration, long-term monitoring, and interventions for recurrence. The arrow represents the closed-loop characteristics of the framework. (B) The multi-purpose characteristics of GBMs in various stages of the cancer perioperative period.

Abbreviations: CSC, cancer stem cell; TME, tumor microenvironment; CTCs, circulating tumor cells; ctDNA, circulating tumor DNA; EVs, extracellular vesicles.s

Confronting the challenges of these multistage perioperative processes, traditional treatment methods remain limited by material monofunctionality and fragmented technological approaches, often yielding suboptimal outcomes.^21,22 Although the recent development of multifunctional strategies has partially addressed these limitations,^23–25 the implementation of a closed-loop system that spans the entire perioperative continuum remains an urgent clinical imperative. The disconnect between current treatment stages increases the complexity of the procedure, increases the risk of collaborative failure, and ultimately limits the prognosis of patients. Therefore, achieving precise intervention throughout the perioperative period through multifunctional, multidisciplinary collaboration and coordinated technological integration remains a widely recognized goal.

Among the many advanced materials available, graphene-based materials (GBMs) have shown great potential for addressing the multi-stage clinical needs of cancer during the perioperative period due to their excellent physical and chemical properties, thereby attracting significant attention (see Chapter 2 for details). Unlike previous reviews that only focused on single applications such as diagnosis, drug delivery, or tissue engineering, this article, for the first time, employs GBM as a unified platform to construct a closed-loop perioperative cancer management framework spanning from preoperative diagnosis to long-term recurrence monitoring and precision intervention, thereby providing systematic guidance for precision perioperative cancer treatment Figure 1B.

Overview of Graphene-Based Materials(GBMs)

GBMs have become one of the most commonly used nanomaterial families in biomedical research due to their unique physical and chemical properties, ease of functionalization, and wide range of bioactive combinations. This chapter first outlines the subtypes and main properties of GBMs, and then explains the rationale for organizing the review by perioperative function rather than material type in this article.

Classification and Key Properties of GBMs

GBMs constitute a family of carbon nanomaterials that share a common sp²-hybridized hexagonal lattice backbone but differ in oxidation state, functionalization, dimensionality, and composite architecture.²⁶ The four most extensively investigated subtypes in biomedical research are graphene, graphene oxide (GO), reduced graphene oxide (rGO), and graphene quantum dots (GQDs).²⁷ In addition, GBMs can be integrated with polymers, hydrogels, or inorganic nanoparticles to form composite systems with tailored properties for specific perioperative applications. Table 1 summarizes the key physicochemical properties and representative perioperative applications of these subtypes,^28,29 and Figure 2 provides a schematic illustration of the GBM structure.

Table 1.

Properties of Different Types of Graphene-Based Materials(GBMs)

GBM type	G	GO	rGO	GQDs	GBM composites	Ref.
Size	μm level	μm level	nm-µm level	<10 nm	Macroscopic	[30]
Surface chemistry	Single‑layer honeycomb lattice, hydrophobic	Oxygen-containing functional groups, hydrophilic	Low oxygen, moderately hydrophobic (high reduction) to moderately hydrophilic (low reduction)	Edge defects, functionalgroups, hydrophilic	Component ‑dependent	[31]
Specific surface Area	~2630 m2/g	600–800 m2/g	800-1200 m2/g	100-500 m2/g		[29,31]
Conductivity	Ultrahigh	Extremely low	Moderate to high	Moderate		[29]
Photothermal performance	Ultrahigh	Low	High	Moderate		[32–34][30,32,33]
Biodegradability	Low to Moderate	Moderate to High	Moderate	High		[35]
Biosafety	Limited evidence	Most extensively studied	Moderate evidence	Most favorable profile		[36,37]

Notes: The biosafety of GBM is highly dependent on multiple factors, including size, surface chemical properties, degree of functionalization, concentration, and exposure pathways, and is currently under active research. Without a clear application background, it is impossible to uniformly classify the biosafety levels of each subtype.

Abbreviations: G, Graphene; GO, graphene oxide; RGO, Reduced graphene oxide; GQDs, graphene quantum dots.

Figure 2.

Schematic illustration of various GBM structures. (A) Graphene. (B) Graphene quantum dot. (C) Three-dimensional porous graphene dressing. (D) Graphene oxide. (E) Reduced graphene oxide. This figure is referenced and adapted from references.^38,39

Graphene, a two-dimensional planar material composed of a single layer of carbon atoms arranged in sp² hybridized states to form a honeycomb lattice, has ultra-high conductivity, thermal conductivity, and mechanical strength, making it suitable for applications such as electrochemical sensing and as a conductive scaffold.^40,41 However, its strong hydrophobicity and tendency to aggregate in physiological environments limit its direct use in biological systems without surface modification.⁴²

GO is an oxidized form of graphite obtained through oxidation and exfoliation, introducing a large number of oxygen-containing functional groups (hydroxyl, epoxy, and carboxyl) at the basal and edge surfaces.³¹ These functional groups make GO hydrophilic and readily dispersible in aqueous media, thereby facilitating its binding to biomolecules, drugs, and targeting ligands. GO exhibits strong near-infrared absorption and fluorescence-quenching properties, hemostatic properties, and promotion of good cell behavior.^43,44 There is also antibacterial activity, mainly attributed to oxidative stress and physical membrane damage, which has been widely documented.⁴⁵

RGO is obtained by GO reduction, which restores the sp²-conjugated carbon network.⁴⁶ Compared with insulating GO, this recovery significantly improves conductivity, and the residual oxygen-containing functional groups retain some hydrophilicity, which is conducive to further biological coupling. Therefore, rGO achieves a practical balance between the excellent conductivity of graphene and the solution processability of GO.⁴⁷ This makes rGO particularly attractive for electrochemical biosensing and photothermal therapy, as its extended sp² region can also enhance near-infrared absorption, thereby significantly improving photothermal performance compared to unreduced GO.^48,49

GQDs are nanoscale fragments of graphene, typically smaller than 10 nm in size and with a thickness of one to three layers.⁵⁰ At edges and defect sites, the sp² carbon network is disrupted, and functional groups introduce additional electronic states. Due to its extremely small size, quantum confinement creates energy gaps.⁵¹ By changing its size, edge shape, or surface functional groups, its photoluminescence properties can be adjusted.⁵² These quantum dots do not contain heavy metals, exhibit low cytotoxicity, and are photostable, making them widely used in fluorescence imaging, sensing, and drug tracking.^53,54 It also exhibits near-infrared absorption, which can be used for photoacoustic imaging. Currently, research is focused on integrating these functions into a nanoparticle platform to enable simultaneous disease treatment and imaging.

GBM based-composite materials, including GBM-polymer hybrid systems, GBM-hydrogel systems, and GBM-inorganic nanoparticle systems, can combine the performance of GBMs with other materials to achieve complementary effects and improve drug efficacy. For example, hydrogels provide an aqueous three-dimensional network for cell encapsulation and tissue regeneration, while a polymer matrix enhances mechanical properties and controlled release capability.⁵⁵ These composite systems significantly expand the multifunctionality of GBM in perioperative applications, ranging from hemostatic sponges and antibacterial dressings to regenerative stents and drug-release implants.⁵⁶ The key challenges lie in the complexity of fabrication and the difficulty of achieving batch-to-batch reproducibility, with biosafety and biodegradability profiles depending on the specific components and composite design.

In summary, there are significant differences in size, surface chemistry, conductivity, and photothermal properties among GBM subtypes, which determine their applicability across biomedical scenarios. However, in the multi-stage, multi-demand continuous process of perioperative management, a single subtype often cannot meet the needs of all stages. Therefore, this article does not elaborate on each GBM subtype but instead focuses on the clinical functions of different stages during the perioperative period. In subsequent chapters, the application characteristics and selection logic of different GBM types in each stage will be discussed separately.

Clinical Rationale for Organizing GBMs by Perioperative Function

Given the diversity of GBM subtypes summarized above, how should these materials be discussed in a clinically meaningful way? This review adopts a function-oriented framework, following the natural sequence of perioperative care rather than GBM subtype (such as GO, rGO, or GQDs) classification. This discussion choice is based on three considerations.

Firstly, perioperative management is essentially task-driven. Surgeons and clinical doctors face specific challenges at different stages, such as achieving clear tumor boundaries, preventing excessive bleeding, avoiding postoperative infections, and promoting tissue repair. These are clinical problems that require specific solutions, not just material issues for clinical applications. Classifying by function makes the review more directly meet the needs of translational researchers and clinical doctors, and the content more readable and operable.

Moreover, different subtypes of GBMs share the same characteristics and can address the same perioperative problems. Many key features, such as photothermal conversion and ease of functionalization, are shared among multiple GBM subtypes (GO, rGO, and GQDs)(see Table 1), mainly due to differences in degree rather than species. This shared attribute means that multiple subtypes of GBM can typically address the same clinical function, thereby unnecessarily limiting discussions based on material types.

Finally, GBMs may provide an integrated treatment strategy that spans all stages of cancer perioperative intervention, achieving an effective closed-loop management system for the perioperative period, based on three fundamental advantages: (1) Inherent multifunctionality. A single GBM (such as GO-based nanostructures) can exhibit hemostatic, antibacterial, regenerative, and anti-tumor properties, making it suitable for hemostasis, wound healing, tissue regeneration, and recurrence prevention.^57–59 (2) Precise programmability and dynamic responsiveness. The tunable surface chemistry and two-dimensional architecture of GBMs enable the design of microenvironment-responsive systems adaptable for applications ranging from preoperative diagnosis to postoperative intervention.^60–62 (3) Physicochemical properties as functional bridges. Core properties like tunable mechanical strength and electrical conductivity serve cross-phase functions. For example, the same conductive network can be used for real-time monitoring during surgery, as well as for applying electrical stimulation to promote tissue regeneration after surgery.⁶³ The development of GBM-based platforms promises to minimize adverse effects associated with multi-material applications, streamline biocompatibility evaluations. Table 2 compares the unique advantages of GBMs in perioperative cancer applications with other materials.

Table 2.

Comparison of the Distinctive Advantages of GBMs Over Other Nanomaterial Classes for Perioperative Cancer Applications

Property	GBMs (Graphene/GO)	Gold Nanoparticles (AuNPs)	Carbon Nanotubes (CNTs)	Polymeric Nanocarriers (PLGA)	Ref.
Electrical Conductivity	Excellent	Good	Excellent	Poor	[64]
Surface Modifiability	Excellent	Good	Moderate	Excellent	[65]
Photothermal Conversion Efficiency	High	High	High	Moderate	[66]
Multifunctional Integration Capability	Excellent	Moderate	Moderate	Good	[65,67,68]
Biocompatibility	Modification ‑dependent	Good	Controversial	Good	[65,67,69]
Perioperative Applicability	Full coverage	Partial coverage	Partial coverage	Partial coverage	[67,70–72]
Primary Limitations	Long‑term safety to be verified	High cost	Toxicity / poor dispersion	Poor mechanical strength, limited functionality	[67,70–72]

Abbreviation: PLGA, poly(lactic-co-glycolic acid).

It should be emphasized that classifying by function does not exclude attention to subtype differences. In subsequent chapters, we will clearly label the GBM subtypes used in each study and, where appropriate, analyze how subtype-specific properties (such as conductivity, surface chemistry, and photothermal efficiency) affect functional outcomes, especially when the literature reports subtype-dependent effects. In short, this article takes function as the macro framework and subtypes as the micro details, complementing rather than opposing each other, to jointly serve a comprehensive understanding of the perioperative application of GBM.

GBMs Enabling Precision Resection in Perioperative Cancer Management

The key to successful cancer surgery lies in precise resection. If the resection is incomplete or inaccurate, it may lead to postoperative recurrence and metastasis, require secondary surgery, increase postoperative management burden, and reduce survival rate. Therefore, precise perioperative diagnosis through edge delineation and accurate resection of tumors and adjacent tissues during surgery are crucial for patient prognosis and survival. GBMs have unique optical/electrical properties, as well as an adjustable surface area, which enable targeted drug delivery, imaging, and response to microenvironments. These features enable preoperative tumor diagnosis through edge delineation in cancer surgery and provide real-time intraoperative imaging guidance, demonstrating great potential for achieving precise tumor resection (Figure 3).

Figure 3.

Schematic illustration of GBMs enabling precision tumor resection. GBMs achieve precise tumor boundary delineation by targeting tumor cell membranes, detecting abnormal molecules in tumor metabolites and microenvironments, and combining multiple imaging methods. During the preoperative stage, GBMs provide static, high-precision tumor localization information for surgical planning. During the intraoperative stage, GBMs are often combined with multimodal imaging to improve accuracy and enable real-time tracking at the minute and second levels, thereby enabling dynamic, real-time surgical navigation and guiding precise resection.

Graphene-Based Precise Preoperative Diagnosis and Construction of Multidimensional Navigation Maps for Tumor Resection

Accurate tumor margin delineation is pivotal for successful oncologic surgery. Inadequate precision during resection may leave residual malignant tissue, leading to poor clinical outcomes such as reduced survival rates, compromised quality of life, and increased healthcare costs from recurrent treatments and prolonged care.⁷³ Good tumor margin identification can improve residual tumor lesions and recurrence/metastasis, reduce secondary surgeries, improve prognosis, and increase patient survival rates.^74,75 Recent advances in molecular-level diagnostics, tumor targeting techniques, and multi-modality imaging enable precise preoperative differentiation between malignant lesions and adjacent normal tissues, which facilitates preoperative tumor margin delineation.^76–78 GBMs demonstrate significant potential for precise preoperative tumor diagnosis and surgical navigation due to their exceptional optical properties, high surface-area-to-volume ratio, tunable interfacial interactions, responsiveness to the tumor microenvironment (TME), and biocompatibility. Through diversified design strategies, GBMs enable precise tumor localization and boundary delineation from molecular-level specific recognition to multi-modality imaging guidance, delivering multidimensional references for surgical planning.

At the molecular diagnostic level, GBMs enable early cancer detection by capturing molecular abnormalities in tumor metabolism and the microenvironment. RGO, with its ultra-large specific surface area and excellent chemical stability, efficiently captures lipids on tissue surfaces while fully preserving their spatial distribution features.⁷⁹ Utilizing tip-contact sampling/ionization mass spectrometry, silicon-nanowire-supported rGO rapidly extracts fatty acids and lipids from liver tissues; predictive models built on ratios of adjacent lipid peaks (eg, C18:1/C18:2) achieve high-accuracy identification of liver cancer tissues (91.7–98.3%). Additionally, its ratio imaging technology significantly enhances spatial resolution at tumor margins. Meanwhile, the PtNi nanoparticle-doped N-rGO nanocomposite material, with a low detection limit of 2.8 × 10⁻⁹ M and a rapid response time of < 6s, can sensitively detect abnormal high expression of hydrogen peroxide (H₂O₂) in the TME, providing molecular evidence for preoperative diagnosis across both metabolic and microenvironmental dimensions.⁸⁰ Environment-responsive graphene probes specifically recognize tumor microenvironmental cues (eg, acidic pH), triggering fluorescence signal switching or enhancement, and enable real-time discrimination between tumors and normal tissues via upconversion luminescence.⁸¹

At the level of targeted recognition and boundary delineation, graphene-based probes enable precise tumor differentiation through tumor-specific mechanisms. GO contains a large number of oxygen-containing functional groups, which can bind to cancer cell proteins, nucleotide fragments, and other biomolecules to achieve targeted recognition.⁸² Utilizing a cell membrane permeability targeting mechanism, graphene-based nuclear-targeted nanoprobes penetrate tumor cell membranes and localize within nuclei with >50% targeting efficiency.⁸³ These probes not only identify early-stage tumors and single-cell-level invasion/metastasis but also provide clear delineation of tumor-normal tissue interfaces, offering direct visual reference for preoperative resection planning.

The breakthrough in imaging technology has further advanced the construction of navigation maps, enabling accurate positioning from single- and multi-modal imaging systems. GO-modified lanthanide nanoprobes combine visible/near-infrared II region luminescent properties to achieve single-cell level miRNA visualization and in vivo tumor-targeted imaging, improving the resolution of deep tissue imaging.⁸⁴ GBMs also possess excellent angiographic capabilities, which can clearly present the distribution and course of blood vessels around the tumor, providing high-resolution tumor and blood vessel navigation maps for cancer surgery. Zhang et al developed a GO conjugated with a folic acid- and gadolinium-labeled dendrimer, which has a relaxation rate (11.6 mM) significantly higher than clinical contrast agents and excellent vascular imaging capabilities, providing high-resolution tumor and vascular navigation maps for liver cancer surgery.⁸⁵ GQDs exhibit superior photostability, inherently low cytotoxicity, and excellent biocompatibility compared to conventional imaging agents such as organic dyes, fluorescent proteins, and semiconductor nanocrystals, positioning them as transformative tools in precision oncology.^86,87 Engineering GQDs enable high-resolution visualization of vasculature and organs via NIR-II imaging (1000–1100 nm), providing a novel metal-free probe for constructing preoperative navigation maps.⁸⁸ Their quantum yield (1.0%) significantly surpasses that of carbon nanotubes (0.4%) and NIR-II-emitting small-molecule dyes (0.3%), while also exhibiting rapid renal clearance and biosafety. This offers critical technical support for demarcating boundaries in deep-seated tumors like gliomas. By integrating GQDs with nanocarriers, prolonged blood circulation and enhanced tumor targeting are achieved, allowing multi-modality imaging coordination of fluorescence, MRI and photoacoustic imaging (PAI) to precisely locate submillimeter residual lesions.⁸⁹ Additionally, fluorescence-quenching probes constructed via π-π stacking between graphene and dyes enhance photoacoustic imaging contrast through fluorescence resonance energy transfer, overcoming tissue penetration limitations of conventional optical imaging.⁹⁰

Collectively, GBMs establish a hierarchically structured preoperative diagnostic system through the coordinated integration of molecular recognition, targeted accumulation, and multi-modality imaging, which lays the pivotal groundwork for precise tumor resection.

GBMs in Intraoperative Real-Time Imaging and Precise Operation Guidance

Preoperative margin mapping provides a precise “strategic blueprint” for tumor resection, yet static imaging cannot anticipate the dynamic intraoperative displacement and deformation of tissues. When surgical manipulation alters tissue dynamics, intraoperative imaging technologies become essential to dynamically capture the tumor’s transient traces in real time, bridging the spatiotemporal divide to achieve the ultimate transition from precise planning to precise execution. This enables accurate tumor resection while minimizing opportunities for residual disease recurrence and metastasis. In recent years, the application of imaging technologies in guiding precise resection of cancer surgeries has received extensive attention and made significant progress.^91–94 GBMs, leveraging their unique physicochemical properties such as quantum confinement effect, surface plasmon resonance, and chemical activity derived from ultra-large specific surface area, possess multi-modality imaging capabilities, including photoacoustic imaging,⁹⁵ fluorescence imaging,⁹⁶ and magnetic resonance imaging.⁹⁷ These properties enable them to guide precise resection of cancer surgeries from single-modality imaging to multi-modality imaging and fusion imaging.

The signal optimization of GBMs for single-modality imaging provides basic guidance technology support for precise cancer resection surgery. Reduced graphene oxide loaded with indocyanine green achieved highly stable loading through π - π stacking interactions. Its strong absorption characteristics in the near-infrared region enhance both fluorescence and photoacoustic signals, thereby solving the problems of easy aggregation and short cycling time associated with free indocyanine green. The circulation time of rNGO PEG/ICG in mice can be maintained for up to 6 hours after intravenous injection, providing long-term imaging guidance for cancer surgical resection.⁹⁸ GO modified with iron oxide nanoparticles utilizes its superparamagnetism and inherent dark color to achieve bimodal lymph node localization in the pancreatic cancer region through MRI and visual dye guidance, enabling preoperative tumor edge mapping and intraoperative visual tracking and localization of lymph nodes from preoperative tumor edge mapping to real-time surgical guidance.⁹⁹

Compared with single-modality imaging, the fusion of multi-modality imaging for GBMs can achieve complementarity by integrating the advantages of different imaging technologies, thereby overcoming the physical limitations of single modalities in terms of tissue penetration depth and spatial resolution, and providing more comprehensive and accurate imaging guidance for surgery. The graphene-gold nanostar composite probe, which integrates photoacoustic imaging (PAI) and MRI, enables precise tumor resection through determining the tumor’s location and boundary in vivo preoperatively via MRI and real-time tracking of probe distribution intraoperatively using a handheld PAI system.¹⁰⁰ This progression from preoperative static localization to intraoperative dynamic tracking reduces the tumor residual rate by 85.71% compared with procedures without handheld PAI guidance.

Furthermore, GBMs exhibit responsive imaging capabilities, significantly enhancing the precision of tumor resection and dynamic intraoperative guidance in cancer surgery. Specifically, the acidity-activated GQD nanotransformers can undergo structural transformation in response to the TME (notably its acidic nature).¹⁰¹ These nanotransformers recognize tumor acidity and disassemble from their compact structure into a state with a diameter exceeding 100 nanometers, which enables retention within the tumor tissue, extending the effective imaging window to 96 hours. Their unique “activation-type” fluorescence/MRI signaling properties allow for dynamic intraoperative differentiation between tumor and normal tissue.

The imaging capabilities of GBMs provide critical guidance for tumor resection during cancer surgery, which enables more precise removal of tumor tissue. This progression from single-modality imaging to multi-modality imaging, and further to microenvironment-responsive dynamic imaging, demonstrates their hierarchical advancement in enhancing surgical precision.

In summary, GBMs can achieve preoperative diagnosis and delineation of the tumor boundary, and provide real-time imaging guidance for surgical resection. This transition from static preoperative planning to dynamic intraoperative guidance helps to accurately remove tumors, thereby improving postoperative management and increasing patient survival rates. Moreover, compared with traditional imaging probes, GBMs can increase the accuracy of tumor edge delineation through multimodal imaging, enable NIR-II imaging to penetrate deep tissues (eg, rGO, GQDs), and offer superior photostability (eg, GQDs), thereby prolonging intraoperative guidance time. However, image-guided precision resection surgery is still in its early stages, and challenges such as balancing imaging depth and resolution remain to be addressed. Future research should focus on optimizing multimodal imaging performance and NIR-II deep-tissue imaging in GBM, improving the signal source in deep tissues and signal stability, thereby achieving more accurate preoperative tumor boundary recognition and persistent, stable intraoperative navigation. GBM-based imaging technology is expected to become a key driver of precision cancer surgery and a component of perioperative closed-loop management systems.

GBMs for Hemostasis in Cancer Perioperative Care

Efficient and rapid hemostasis is the fundamental guarantee of surgical safety, serving as an imperative prerequisite for successful wound healing and subsequent tissue engineering repair. Due to complicated factors of abnormal tumor vasculature, extensive tissue damage, coagulation dysfunction, and adjuvant chemotherapy, patients undergoing cancer surgery face a significantly elevated risk of bleeding during the whole perioperative period^102,103 Complex and difficult-to-control hemorrhage remains a formidable challenge in this setting. GBMs, leveraging their unique physicochemical properties (eg, porous structure, abundant surface functional groups, high specific surface area, and excellent mechanical strength)¹⁰⁴ demonstrate significant advantages in managing perioperative hemostasis in cancer surgery through mechanisms involving physical adsorption and induction of bioactive hemostasis (Figure 4). They hold great promise, particularly for addressing diffuse and uncontrollable bleeding during the perioperative period, which establishes them as an ideal material for perioperative hemostasis in cancer surgery.

Figure 4.

GBMs in hemostatic therapy for cancer perioperative care. (A) The multiple factors driving cancer-related bleeding. (B) Schematic representation of the dual hemostatic mechanisms of GBMs: (1) Physical absorption. The three-dimensional porous structure of GBMs rapidly absorbs plasma, thereby concentrating blood cells and platelets to accelerate the initial coagulation cascade. (2) Biological effects. The abundant oxygen-containing functional groups and negative surface charge of GBMs actively activate multiple endogenous coagulation pathways and promote platelet adhesion/aggregation, achieving synergistic hemostasis. The upward arrow (↑) in (B) (2) indicates an increase in Ca²⁺ concentration. As shown, GO directly stimulates Ca²⁺ release or activates platelet Src kinase, leading to elevated Ca²⁺levels. The physical absorption mechanism was summarized from,¹⁰⁵ and the biological effect mechanism was summarized from.^106–109

Inherent Pro-Hemostatic Properties of GBMs

GBMs inherently possess hemostatic capabilities. In the context of physical mechanisms, studies have demonstrated that graphene leverages its high specific surface area and three-dimensional porous structure to efficiently aggregate blood cells through physical adsorption and enhances the material’s mechanical stability, thereby significantly accelerating coagulation to achieve rapid hemostasis.¹¹⁰ Moreover, graphene-based porous sponges (such as GO sponges) can quickly absorb plasma from the blood, concentrate platelets and coagulation factors, and accelerate local thrombus formation.¹⁰⁵ Compared to traditional hemostatic sponges (such as gelatin sponges), graphene-based porous sponges, which are fast-absorbing hemostatic sponges, offer significant advantages in treating diffuse bleeding caused by abnormal tumor blood vessels, coagulation dysfunction, or extensive tissue trauma during cancer surgery. Quan et al developed a porous cross-linked graphene oxide sponge via a hydrothermal-microwave hybrid method, demonstrating rapid plasma adsorption and blood cell concentration through its hierarchical porous structure, which achieved coagulation within 60 seconds in vitro and effective hemostasis in 2–4 minutes in rodent models, exhibiting excellent biocompatibility for potential application in managing diffuse hemorrhage during oncological procedures.¹¹¹ Li et al developed a graphene montmorillonite composite spong via a hydrothermal microwave combined method, whose graded porous structure significantly accelerates coagulation by rapidly adsorbing plasma and concentrating blood cells/platelets (completed within 2 minutes in in vitro dynamic whole-blood experiments), achieves hemostasis within 85 seconds in a rabbit artery injury model, confirms no thrombus formation via CT angiography, and demonstrates excellent biocompatibility in cytotoxicity tests, thus providing a safe and efficient novel solution for controlling diffuse bleeding in trauma treatment.¹¹²

Regarding the biological aspect, GBMs can activate platelets and amplify the coagulation cascade, offering a promising strategy to mitigate chemotherapy-associated hemorrhagic complications. Thrombocytopenia arising from underlying comorbidities, infections, medications (including chemotherapy/radiotherapy), particularly chemotherapy-induced thrombocytopenia, poses significant clinical challenges for surgical resection and perioperative management in cancer patients.^113–115 Prior research has established that GO nanosheets activate platelets and induce potent aggregation through oxygen-containing functional groups (eg, hydroxyl, carboxyl), thereby achieving hemostasis, while a reduction in these oxygen functionalities markedly diminishes their capacity to stimulate platelets.¹⁰⁶ The research results of Zhang et al showed that GO can enhance the expression of CD62p (one of the important markers of platelet activation) and enhance platelet activation ability by promoting the release of intracellular Ca²⁺.¹⁰⁷ Moreover, GO strongly promotes platelet aggregation and thrombus formation by activating platelet Src kinase, stimulating Ca²⁺ release, and modulating surface charge distribution, whereas rGO exhibits weaker hemostatic activity but improved safety due to its diminished surface charge.¹⁰⁸ Furthermore, studies demonstrated that the carboxyl groups on GO confer negative charges, which may activate the conversion of coagulation factor XII to XIIa, thereby promoting the intrinsic coagulation pathway and significantly shortening clotting time to achieve rapid and efficient hemostasis.¹⁰⁹

GBMs, particularly GO, demonstrate exceptional hemostatic performance through synergistic physicochemical properties and bioactive mechanisms, showing promising potential in rapid physical adsorption-based hemostasis, platelet activation, and intrinsic coagulation cascade stimulation during perioperative cancer care. However, the hemostatic efficacy of standalone GBMs may be limited in complex pathological microenvironments (eg, tumor-associated coagulation dysfunction or drug-induced thrombocytopenia). Future studies should focus on developing graphene-based composite hemostats by integrating them with functional biomaterials to enhance their synergistic effects, biosafety, and clinical applicability in perioperative cancer management.

Functionalized GBMs with Enhanced Hemostatic Performance

GBMs, characterized by their high specific surface area and abundant functional oxygen-containing groups on their surface, exhibit exceptional chemical modifiability. Through functionalization strategies, their hemostatic properties can be precisely tailored to greatly improve the limitations of coagulation efficiency and biocompatibility, serving as a new generation of efficient, safe, and stable hemostatic materials for perioperative cancer management.

Functionalized GBMs hold significant potential for constructing bioinspired hemostatic agents to address uncontrolled bleeding during cancer resection surgeries. In a groundbreaking study, Farrokhi et al engineered a GO-based biomimetic hemostat by covalently grafting fibrinogen-mimetic peptides (GRGDS/H12) to mimic natural coagulation mechanisms.¹¹⁶ This nanomaterial demonstrated rapid, targeted hemostasis (achieving clot formation within 12 seconds with < 1.4% blood loss) through agonist-triggered platelet aggregation, while exhibiting ultralow hemolytic activity (<1%). Its microenvironment-responsive activation mechanism and biocompatibility position it as a promising candidate for precise hemorrhage control in oncological surgeries, offering a safe and efficient strategy to manage life-threatening intraoperative bleeding. Moreover, inspired by the anisotropic structure of the Euryale Ferox stem, Xie et al engineered a compressible anisotropic sponge composed of quaternized cellulose, xanthan gum, and rGO, which synergistically integrates rapid fluid absorption, mechanical reinforcement, coagulation cascade activation, and antibacterial activity for hemorrhage control, demonstrating in rat liver defect models a 34-second hemostasis time with 85% blood loss reduction through rapid shape recovery post-compression, offering a promising strategy for managing non-compressible bleeding in oncological surgeries.¹¹⁷

Functionalized GBMs with optimized pore size can enhance hemostatic performance, as the microporous structure plays a crucial role in blood absorption and wound exudate management. The pore structure of hemostatic matrix (including density and size parameters) directly determines its liquid absorption rate, which in turn regulates the hemostatic performance of the material through liquid management mechanisms. Excessively large pores compromise fluid retention, whereas insufficient porosity limits absorption capacity, both hindering effective hemostasis. By utilizing the inherent properties of graphene, such as high specific surface area and adjustable surface functionality, three-dimensional porous hemostatic materials can be constructed.¹¹⁸ These three-dimensional (3D) materials can accelerate the aggregation of red blood cells and platelets, thereby improving hemostatic effects and promoting tissue regeneration processes. At the same time, they can also meet various clinical needs, such as wound management during the perioperative period of complex tumor surgery and treatment of coagulation dysfunction. The addition of graphene oxide initially increases the porosity of the hemostatic sponge, but this effect reverses after exceeding a certain concentration; the optimal deposition of graphene oxide on the surface can achieve controllable amplification of pore structure, thereby improving the liquid absorption rate and hemostatic performance by enhancing capillary action and platelet activation pathways.¹¹⁹ In addition, previous studies have demonstrated that physically blending GO with other materials can effectively expand the microporous architecture of hydrogels, with pore size increasing from 9.5±1.9 μm to 21.0±8.8 μm, which significantly enhances the liquid absorption capacity of these functionalized GBMs and consequently improves their hemostatic performance.¹²⁰ Du et al found that the addition of graphene oxide increases the porosity of composite hemostatic sponges. The liquid absorption capacity increases with the graphene oxide content within a specific range, forming more absorption channels and significantly enhancing the capture and retention of red blood cells and platelets.¹²¹ Therefore, GBMs, especially GO, can optimize the porosity-based pore size of hemostatic materials to enhance the hemostatic ability of functional graphene-based hemostatic materials, thereby improving the foundation for efficient and rapid hemostasis during the cancer perioperative period.

In addition to optimizing the pore structure of hemostatic materials, GBMs can enhance mechanical properties and biocompatibility through functionalization, improving the hemostatic efficacy of sponges via bioactivation.^122–124

In summary, GBMs can not only achieve hemostatic effects in terms of physical and biological activity, but also enhance hemostatic ability through functional modification. The dual hemostatic efficacy endows GBMs with great potential in complex and difficult hemorrhage scenarios to control bleeding during the perioperative period of cancer, with functional modifications that may further optimize their performance for perioperative care in oncological surgical interventions. Furthermore, their functionally modifiable surfaces and diverse morphological structures allow for further loading with antibacterial/wound-healing promoting agents or the formation of multifunctional porous scaffolds, thereby laying the groundwork for subsequent wound healing and tissue regeneration. This highlights the pivotal role of GBMs as a versatile hemostatic platform in the comprehensive perioperative management framework.

GBMs for Synergistic Antibacterial Therapy and Smart-Responsive Wound Healing in Cancer Postoperative Care

Postoperative wound healing is an important bridge between short-term surgical recovery and long-term management, and its outcome fundamentally affects tissue function reconstruction and risk transfer, therefore requiring long-term monitoring. The wound management of cancer patients during the perioperative period faces enormous challenges, mainly due to the combined effects of various factors such as cancer itself, immune dysfunction caused by treatment (especially weakened anti-infection ability), multidrug-resistant infections, poor metabolic status, tissue damage, vascular dysplasia, cell proliferation inhibition, and inflammatory microenvironment. These factors collectively impede healing and threaten survival. Bacterial infections often delay wound healing, making antibacterial treatment an essential and crucial step in the process. Based on the above, cancer-related wound healing is influenced by multiple factors, and a single method is difficult to meet the needs of cancer wound healing. A comprehensive strategy of multifunctional collaboration will be the future direction of cancer wound healing. This comprehensive strategy will be crucial for simultaneously addressing the intertwined challenges of drug-resistant infections, immune suppression, healing disorders, and dysregulation of the tumor microenvironment. GBMs with their own multiple antibacterial functions and healing-promoting properties, as well as highly adjustable structural height, have become an ideal choice for building such a collaborative platform. Their core value lies in their ability to use multiple materials and synergistically promote wound healing.

GBMs Enable Antibacterial Activity and Wound Healing via Synergistic Mechanisms

This section focuses on the intrinsic antibacterial and pro-healing functions of GBMs, arising from their inherent physicochemical properties. Some of these functions, such as photothermal conversion and photocatalysis, may require external stimuli (eg, NIR irradiation or simulated sunlight) to be activated. However, they are discussed here as intrinsic material properties because the stimuli merely trigger the materials’ inherent capabilities, rather than constituting programmable, on-demand, or adaptive systems. The latter category, involving smart-responsive design, is the focus of Smart-Responsive GBMs for On-Demand Modulation of Dynamic Wound Healing in Cancer Postoperative Care.

GBMs possess multi-mechanism antibacterial and wound-healing-promoting properties (Figure 5), which establish a solid foundation for synergistic treatment of infection and wound healing during the perioperative period of cancer. In terms of antimicrobial mechanisms, first, GBMs physically kill bacteria via their sharp nanostructures, which penetrate and disrupt bacterial cell membranes, causing content leakage and death.^125,126 GO and rGO have a large surface area that wraps or adsorbs bacteria, preventing them from absorbing nutrients and achieving bactericidal effects.¹²⁷ These GBMs’ physical bactericidal ability is not only unaffected by the complex immune system of cancer patients, but also effective against drug-resistant and sensitive strains.¹²⁸ This is beneficial for cancer patients who have suffered severe damage to their endogenous anti-infective ability due to the immunosuppressive microenvironment caused by chemotherapy and other treatments. Second, The antibacterial properties of GBMs are closely related to their regulation of reactive oxygen species (ROS). On the one hand, GO can induce oxidative stress, producing ROS, disrupting bacterial cell membrane integrity, and exerting bactericidal effects.¹²⁹ On the other hand, after cancer surgery, the wound itself may be in a microenvironment of high ROS and high inflammation. If pro-oxidative GO is used without screening, the additional ROS produced may exacerbate the inflammatory response and be detrimental to tissue healing. However, it is worth noting that rGO and specifically sized nano GO also exhibit ROS scavenging activity.¹³⁰ Their sp² carbon skeleton can neutralize excess ROS through electron transfer and free radical addition, and their large specific surface area can also adsorb pro-inflammatory factors.^131,132 Therefore, postoperative wound healing in cancer requires selecting appropriate GBM types, sizes, or wound-healing stages. In addition, for radiotherapy-damaged skin that lacks an intact stratum corneum, GBMs can form a conformal physical barrier, effectively isolating exogenous pathogens. Finally, GBMs can non-invasively generate high temperatures over a short period, destroy the intact structure of bacteria, achieve bactericidal effects, prevent bacterial resistance, and benefit the treatment of perioperative infected wounds in cancer patients.^133,134 Regarding pro-healing mechanisms, GBMs promote angiogenesis to counteract cancer/chemoradiotherapy-induced vascular reduction, thereby improving wound nutrition and oxygen supply.^135–137 And, their topological structure can enhance cell adhesion, proliferation, differentiation, and migration behaviors, contributing to wound re-epithelialization and granulation tissue formation.^138,139 Furthermore, functionalized variants can serve as drug carriers to load therapeutic agents that target inflammatory cells, regulating the microenvironment for targeted anti-inflammatory effects to promote wound healing.^140,141

Figure 5.

Schematic diagram of the antibacterial mechanism and wound healing promotion of graphene-based materials. (A) Antibacterial mechanism. GBMs mainly exert antibacterial effects through the following ways: (1) sharp edges penetrate bacterial cell membranes, causing leakage of contents; (2) GBMs generate excessive ROS due to self-induced or light-induced oxidative stress; (3) Photothermal effect destroys bacterial cell membrane; (4) Physically enveloping bacteria to prevent them from absorbing nutrients from the outside world. (B) Promote wound healing. In infected wounds, the intelligent photothermal responsive GBM wound dressing regulates infrared light irradiation as needed, synergizes multiple antibacterial mechanisms to eliminate bacteria, reduces wound inflammation, promotes tissue regeneration, and accelerates wound healing. This figure is referenced and adapted from references.^134,142

Based on these characteristics, GBMs significantly enhance perioperative wound repair in cancer patients through synergistic antibacterial and healing mechanisms, thereby addressing the multiple challenges of cancer-related surgical wound healing simultaneously. GO quantum dots, upon NIR irradiation, generate localized hyperthermia via their intrinsic photothermal conversion, disrupting bacterial membranes and activating the ERK1/2-SILT3 pathway to induce H-shaped angiogenesis, thereby synergistically promoting chronic wound healing.¹⁴³ GO utilizes its high surface area and conductivity to remove reactive oxygen species, alleviate oxidative stress, enhance cell adhesion, and promote fibroblast migration. Meanwhile, as a sustained-release carrier, it prolongs anti-inflammatory effects and promotes collagen synthesis.¹⁴⁴ This establishes a triple synergistic mechanism of antibacterial protection, cell behavior regulation, and sustained drug delivery, collectively optimizing the wound microenvironment to accelerate healing. Graphene can enhance endogenous electrophysiological functions by increasing inter-wound electrical currents, thereby modulating fibroblast activation and promoting healing.¹⁴⁵ Concurrently, when modified with sulfated hyaluronan via π-π stacking, it can drive M2 macrophage polarization and suppress inflammation. Similarly, Li et al developed graphene-spiky silica heterostructure nanoparticles, utilizing their unique nano-bridge effect while harnessing graphene’s inherent antibacterial properties (both chemical and physical) and cell-proliferation/migration enhancement mechanisms, thereby accelerating wound healing across all four major phases: hemostasis, inflammation, proliferation, and remodeling.¹⁴⁶ Leveraging rGO’s photothermal antibacterial effect and its conductivity (which promotes cell migration and accelerates healing), Wang et al constructed GVG-Zn cryogels from gelatin methacrylate, β-cyclodextrin-modified rGO, 1-vinylimidazole, and Zn²⁺, integrating hemostatic, antibacterial, conductive, and vasculogenic functions to accelerate wound healing.¹⁴⁷ To address skin damage from radiation cancer therapy, Zhou et al constructed the SPI-SH-GA@PGO bio-gel, leveraging GO’s physicochemical antibacterial properties and polydopamine-reduced GO’s ability to promote angiogenesis and reduce apoptosis by scavenging ROS, synergizing with the bioactivity of SPI-GA-SH to significantly accelerate radiation-induced skin injury healing.¹⁴⁸ Leveraging the inherent physical antibacterial properties of GO alongside its drug-loading capability, Hao et al constructed the IFI6-PDA@GO/SA system.¹⁴⁹ This system exhibits antibacterial activity, promotes cell migration and angiogenesis, and inhibits apoptosis, thereby ameliorating the immune microenvironment and facilitating the repair of radiation-induced skin injury wounds.

In summary, GBMs, leveraging their “multi-purpose” nature as described, can simultaneously address the multiple challenges of cancer perioperative wound infection through the synergistic action of their antibacterial and pro-healing mechanisms. These challenges include tissue damage, impaired angiogenesis (or vascularization), inhibited cell proliferation, multidrug-resistant bacterial infections, as well as postoperative inflammatory microenvironments and radiotherapy-induced skin injuries. This makes them an ideal intelligently engineered material for future clinical applications in perioperative wound management for cancer patients.

Smart-Responsive GBMs for On-Demand Modulation of Dynamic Wound Healing in Cancer Postoperative Care

Compared to single-functional materials, GBMs with synergistic antibacterial and pro-healing mechanisms significantly enhance wound repair efficacy. However, their static functional release modes struggle to adapt to the dynamic evolution of postoperative cancer wound microenvironments (eg, sudden infections, inflammation resolution, and healing-phase transitions), posing challenges such as imprecise modulation and potential side effects. Therefore, leveraging graphene’s strong modifiable surface area and its synergistic antibacterial/pro-healing mechanism, the design of materials endowed with “perception-response” capability becomes imperative. Such materials can intelligently recognize changes in wound status and dynamically adjust their antibacterial and healing behaviors, representing a cutting-edge innovation and inevitable development direction for achieving more efficient, safe, and personalized wound management.

Smart photothermal-responsive graphene materials offer dynamic wound healing control and skin-adaptive system synchronization through on-demand modulation, enhancing postoperative cancer wound recovery precision. On-demand, photothermally tunable GBMs enhance both efficacy and precision in dynamic wound healing. A groundbreaking study by Yan et al exemplifies this approach by designing a Janus hydrogel combining GO and the Chinese-medicine-derived molecule rhein, which synchronizes light-triggered antimicrobial action with adaptive wound closure to address the dynamic challenges of infected wounds.¹⁵⁰ In addition to antibacterial applications, photothermal-responsive GBM systems are designed for remote, precise regulation of cell behavior during wound-healing processes. Yu et al developed a PLA/UA/GO nanofiber membrane that leverages GO’s photothermal effect as an external control signal to dynamically regulate macrophage M1/M2 polarization via the integrin RhoA-ROCK1 pathway, thereby promoting wound healing.¹⁵¹ Lai et al engineered a self-responsive multifunctional wound dressing comprising a poly(L-lactic acid) piezoelectric layer coupled with rGO photothermal components, which achieves controlled antibacterial action and oxygen-supplying capacity through precisely modulated ultrasound and near-infrared irradiation durations, thereby accelerating wound healing via dual piezoelectric-photothermal activation.¹⁵² Ding et al developed a GO-based hybrid hydrogel scaffold that integrates GO’s photothermal responsiveness, conductivity, and tunable mechanical properties to achieve multifunctional synergistic therapy, including on-demand drug release, photothermal antibacterial effects, and angiogenesis promotion, significantly enhancing dynamic healing of infected wounds.¹⁵³ Beyond static photothermal regulation, the next generation of graphene-based wound therapies focuses on adaptive functionality. Recently, a bio-inspired self-regulating electronic skin system has been reported that mimics the human skin’s thermosensory-feedback mechanism to achieve dynamic temperature control while significantly promoting wound healing, featuring a flexible, efficient, and safe closed-loop temperature regulation system with laser-induced graphene as its core component combined with polymer-based PTC thermistors.¹⁵⁴ A multifunctional hydrogel dressing for treating MRSA-infected dynamic wounds was developed by Zhao et al, with its core innovation lying in the use of phenylboronic acid-modified rGB to endow the material with excellent skin-adaptive properties and dynamic wound healing performance, while combining mild photothermal antibacterial therapy and bacterial capture capabilities to achieve efficient and safe wound management.¹⁵⁵

Parallel to its established photothermal responsiveness and skin-adaptive properties, the graphene-based dressing exhibits precise microenvironmental recognition capabilities (such as pH response and oxidative stress response) to address the complex healing challenges of postoperative cancer wounds. Liang et al developed a pH/glucose dual-responsive hydrogel dressing that enables localized drug release in acidic environments to enhance chronic diabetic wound healing, establishing a foundational design paradigm for pH-triggered drug delivery in post-cancer resection wound care¹⁵⁶ Cui et al developed an intelligent dressing based on GQD-decorated luminescent porous silicon, which enables precise drug release in response to the diabetic wound microenvironment (H₂O₂ oxidative stress and acidic pH), while leveraging GQDs to enhance drug-loading capacity and FRET-based ratiometric fluorescence for real-time wound monitoring, offering an innovative strategy for microenvironment-responsive therapy in chronic wounds, including post-cancer surgical wounds.¹⁵⁷

In summary, through ingenious design of photo-responsiveness and microenvironment-responsiveness, GBMs have achieved a paradigm shift from “static multifunctional synergy” to “dynamic intelligent on-demand regulation”. The ability to perceive wound conditions and automatically adjust functional outputs may provide a revolutionary solution to the core challenges in perioperative wound management for cancer patients. It is worth noting that its intelligent response capability provides a foundation for monitoring and precise intervention in the closed-loop management of postoperative care. In addition, the inherent modifiability of GBM is expected to upgrade this intelligent response platform into a comprehensive postoperative management system that can achieve wound condition monitoring, infection/recurrence warning, and ultimately achieve on-demand precision treatment. This system will become a key node in the entire perioperative closed-loop framework.

Graphene-Enabled Physical Instruction for Structural and Functional Regeneration in Perioperative Cancer Therapy

Cancer radical surgeries (eg, amputation, organ resection, extensive dissection) are designed to eradicate lesions but result in massive, irregular, and poorly defined tissue defects during the perioperative period, far exceeding those in benign surgeries. Repairing these defects and restoring function are crucial for improving patients’ postoperative quality of life and represent the ultimate reflection of successful surgical treatment. GBMs, with their unique physical properties such as tunable structure, exceptional mechanical properties, and excellent conductivity, offer novel possibilities for actively guiding cell behavior, microstructural reassembly, and functional maturation during tissue regeneration following radical cancer surgery. They represent a highly promising solution for post-operative tissue repair.

Graphene-Based Platforms Meet Specialized Regeneration Needs in Oncologic Resection Defects

Cancer surgery necessitates deliberate resection of tissues at risk for recurrence, resulting in uniquely extensive and complex postoperative defects with irreversible loss of microarchitecture, distinct fundamentally from localized damage caused by conventional trauma. Critical-sized bone defects exceeding 3 cm exhibit limited regenerative capacity, significantly increasing the risk of complications and potentially leading to functional impairment.¹⁵⁸ Radical cancer surgery, such as osteosarcoma resection, while essential for tumor eradication, inevitably creates complex composite defects with extensive osseous and soft tissue loss; this severely compromises intrinsic regenerative capacity, leading to high complication rates, significant morbidity, and major surgical challenges.^159,160 Furthermore, distinct from routine surgical resection, the infiltrative growth pattern of tumors, the requirement for wide surgical margins, and irregular tumor contours collectively cause irregular postoperative tissue defects. This substantially increases reconstructive complexity and elevates material requirements: for instance, filling irregular bone voids necessitates injectable or patient-specific implants that must combine customized conformation to the defect geometry with appropriate mechanical properties.^161,162 Moreover, bone features a rigid calcified outer cortex and an interconnected yet architecturally distinct trabecular interior, both characterized by intricate vascularization.¹⁶³ Consequently, the resection process inevitably compromises sophisticated microarchitectures, including trabecular networks, vascular plexuses, nerve bundles, and muscle fiber fascicles,¹⁶⁴ with nerve bundle destruction frequently proving irreversible. In addition, due to the wide and irregular scope of cancer radical surgery, the surgery usually involves multiple types of tissues. This requires the tissue regeneration scaffold to have adaptability to different physical and chemical properties of tissues at the interface. Therefore, compared to other wound sites, the tissue damage at the site of cancer resection is much more complex. This may seriously damage the body’s functions, manifested as severe weight-bearing bone defects leading to restricted movement, nerve damage causing sensory loss and numbness, and muscle damage leading to impaired motor function.

Addressing complex tissue defects and functional loss resulting from cancer resection surgery, tissue regeneration engineering has emerged as a crucial treatment strategy. However, traditional biomaterials have shown significant limitations in handling complex tissue defects after radical cancer resection. Bioceramics have brittleness and poor mechanical properties.¹⁶⁵ The biodegradation rate of metal materials, such as magnesium alloys, is very fast, which affects the mechanical support in the later stages.^166,167 The challenge faced by polymer scaffolds is that natural polymers have weak mechanical strength and large batch differences, while synthetic polymers may cause inflammation through their degradation by-products.^168,169 These inherent defects fundamentally limit the application of traditional biomaterials in three key areas: the recovery of complex damaged tissues, the provision of gradually changing mechanical properties from hard bones to soft muscles, and the functional regeneration of electroactive tissues, including nerves and muscles. These types of materials usually only serve as “passive fillers” and lack the “intelligence” required for coordinated, precise tissue regeneration and functional recovery. Therefore, there is an urgent need for a new generation of biomaterials that can actively provide physical instructions to guide on-demand cell arrangement and assembly, thereby reconstructing complex microstructures and restoring physiological functions.

GBMs possess exceptional physical properties, notably structural programmability (eg, customizable topological configurations and porous three-dimensional scaffolds), outstanding mechanical properties, and intrinsic conductivity.^170–173 These characteristics make them ideal candidates for solving complex challenges in tumor reconstruction, particularly in terms of functional recovery and repair of extensive tissue defects after cancer resection surgery.

Harnessing Graphene’s Physical Cues to Direct Microstructural Reassembly and Functional Maturation in Tissue Regeneration

GBMs, with their unique physical properties, may become an ideal material for tissue regeneration after cancer resection. GBMs have regular micro- and nano-topological structures that can accurately guide cellular behavior, including directed migration, proliferation, and differentiation. Its adjustable hardness enables it to adapt to various tissues, thereby facilitating the recovery of microstructure at tissue interfaces. In addition, its excellent conductivity helps to accelerate functional recovery, and is further enhanced through the synergistic effect of the designable three-dimensional porous scaffold. These characteristics make GBMs an ideal platform for addressing the complex challenges of perioperative tissue regeneration in cancer treatment (Figure 6).

Figure 6.

Graphene-Based Physical Cues Directing Tissue Regeneration for Perioperative Cancer Therapy. (A) Topographical cues guide cellular behaviors. Schematic showing that cells contact and adhere to graphene-based micropatterned topographies. The physical cues from the patterned graphene substrates direct cellular alignment, migration, proliferation, and differentiation. (B) Graphene-based biomimetic trabecular bone scaffold for reconstructing biological networks. The 3D graphene-based scaffold is designed to reconstruct biological networks within post-tumor resection defects, providing a favorable spatial and microenvironmental niche for nutrient transport, cell growth, as well as vascular and neural regeneration. (C) Tunable stiffness and functional recovery. The tunable stiffness of GBMs allows for the fabrication of scaffolds with mechanical properties matched to different tissues, thereby promoting tissue regeneration. Additionally, the inherent electrical conductivity of GBMs facilitates axonal regeneration of neural cells, ultimately contributing to the restoration of tissue structure and function after cancer surgery. This figure is referenced and adapted from references.^174–177

Patterning Micro/Nanoscale Topological Structures

GBMs can serve as topographical regulators that direct cellular behavior through precisely engineered surface features. These physical cues guide the directional migration and proliferation of normal tissue cells, thereby accelerating the healing of large, irregular wounds following tumor resection surgery. Research shows that modified graphene oxide can be fabricated into on-demand micro-patterned interfaces, enabling physical contact and regulation of collective cell migration and growth.¹⁷⁸ Shin et al fabricated a micropatterned GO substrate via self-assembly and photolithography.¹⁷⁹ The nano-topographical wrinkles of GO directly guided cytoskeletal reorganization through physical contact, augmenting focal adhesion formation. Concurrently, GO’s high specific surface area adsorbed abundant serum proteins, creating a pre-adsorptive layer that amplified cell-substrate physical interactions. This study confirms that GO’s physical topological pathway independently enables subcellular spatial programming of cells. Using self-assembly and photolithography, Park et al engineered an anisotropic rGO substrate with micropatterned stripes.¹⁷⁴ MSCs cultured thereon exhibited spontaneous, highly ordered alignment directed by rGO’s repulsive topological interface, undergoing spatial confinement-mediated mechanotransduction to differentiate into functional smooth muscle cells without exogenous inductive factors. Kang et al prepared patterned rGO with a precise and controllable nanoscale surface topology.¹⁸⁰ This nanoscale morphology directly provides physical guidance for cell behavior, such as cell arrangement, and is not affected by cell type. These carefully designed reduced graphene oxide nanostructures can provide a programmable cellular microenvironment, enabling efficient and biochemical factor-free promotion of cancer defect tissue regeneration. Therefore, on-demand, controllable, and precise manufacturing of graphene-based topological structures can serve as physical guiding signals to spatially guide cell behavior, enabling the initial precise programming stage of tissue regeneration.

Tunable Stiffness Synergistic Electrical Properties

Beyond topological guidance, the tunable stiffness and exceptional conductivity of GBMs synergistically orchestrate tissue microstructural reassembly and functional maturation. The dynamic interplay between these two properties is pivotal. On the one hand, the stiffness of GBMs themselves is designable and tunable.^181–183 Adjusting their concentration, layer thickness, and other conditions enables precise control over the stiffness of graphene-based composite materials used in tissue engineering.¹⁸⁴ This flexibility enables GBMs to achieve gradient stiffness matching, spanning from rigid tissues like bone to moderately hard articular tissues,^185,186 and further to soft tissues such as neural and adipose tissues,^187,188 thereby mimicking the hardness values of diverse human tissue scaffolds^189,190 The stiffness gradient of this material is designed to optimally match multilayer tissue interfaces, thereby promoting microstructural restoration at sites damaged by cancer resection surgery. Moreover, these mechanical cues profoundly influence cell adhesion, spreading, and proliferation, which guide the initial stages of microstructural reorganization by determining cell morphology and tissue organization.¹⁹¹ On the other hand, the excellent conductivity of GBMs enables them to enhance the electrical conductivity of tissue engineering scaffolds.¹⁹² This allows them to mimic the natural electrical activity of tissues and regulate the local electrical microenvironment of electroactive tissues. For example, they can promote the recovery of neural tissue through mechanisms such as stimulating axonal regeneration, myelin formation, and promoting neural differentiation of adipose-derived mesenchymal stem cells (ADMSCs) through electrical signals.^193,194 In addition, they can enhance the transmission of electrical signals between cells, thereby promoting the differentiation of muscle cells.¹⁹⁵ This is of significant importance for the functional maturation of electroactive tissues. Moreover, the on-demand regulation of both electrical signals and stiffness in GBMs enables their synergistic coordination, which is more conducive to mimicking human tissue growth and development.^196,197 Therefore, GBMs can promote functional maturity by physically guiding and coordinating the reorganization of tissue microstructures through the synergistic effect of adjustable stiffness and abnormal conductivity.

Engineered 3D Porous Scaffolds

Notably, graphene-based 3D scaffolds exhibit an engineerable interconnected porous network that serves as a functional amplifier, spatially resolving and amplifying cue transmission to enhance these effects. In regulating cellular behavior, the three-dimensional (3D) interconnected porous structure of GBMs enhances cellular activities by providing the spatial foundation for cell-cell connectivity and promoting the formation of 3D cellular networks.¹⁹⁸ Furthermore, its macropores promote bone tissue growth, capillary formation, and nutrient/waste transport, while micropores and mesopores enhance cell adhesion and proliferation by promoting the adsorption of extracellular matrix (ECM).^175,199 Regarding material stiffness, the structure enhances biomechanical properties. Nanoscale pores offer greater mechanical stability than macropores (>100 μm).¹⁷⁶ Moreover, the porous polyacrylamide gel scaffold containing water exhibits excellent mechanical properties, indicating that to achieve the best mechanical support, it is necessary to coordinate the pore diameter, porosity, and Young’s modulus.²⁰⁰ Thus, rational pore design improves mechanical stability. Electrically, the conductive architecture provides electrophysiologically activatable pathways for axonal regeneration, thereby optimizing the reintegration of neural networks.¹⁷⁷ Additionally, the highly permeable interconnected pores of the 3D graphene-based porous scaffold provide pathways for neovascularization, enabling capillary infiltration into the scaffold interior and thereby supplying blood to the new tissue.²⁰¹

In summary, GBMs utilize their physical clues to make them an excellent platform for the regeneration therapy of complex tissue during the perioperative period of cancer. Its main advantage is that it can utilize its advanced physical properties to achieve: (1) programmable micro/nano topography to guide cell behavior (directed migration, proliferation, and differentiation); (2) Adjustable hardness meets specific mechanical requirements of the organization to restore the microstructure of the interface; (3) Collaborative electrical characteristics accelerate functional recovery; And (4) engineered three-dimensional porous scaffolds. Moreover, based on these excellent physical characteristics, three-dimensional intelligent responsive regenerative scaffolds with integrated monitoring functions are expected to become a future development trend, achieving a closed-loop process from successful perioperative management to tissue defect repair and long-term monitoring.

Graphene-Based Monitoring-Therapeutic Integrated Systems for Perioperative Control of Cancer Recurrence and Metastasis

Recurrence and metastasis of malignant tumors after surgical resection remain the primary challenges leading to resection treatment failure,^201–204 which are major contributors to cancer-related mortality^205,206 The early and sensitive detection of recurrence and metastasis, followed by timely and precise intervention, constitutes the ultimate challenge in determining patients’ long-term survival. The effectiveness of this critical phase serves as the litmus test for evaluating the overall success of perioperative management strategies. Owing to their exceptional physicochemical properties, GBMs demonstrate outstanding capabilities in liquid biopsy for perioperative monitoring of cancer recurrence/metastasis, and precision intervention therapy, positioning them as ideal platforms for integrated systems targeting metastatic progression.

Liquid Biopsy Monitoring for Perioperative Recurrence and Metastasis of Cancer

Liquid biopsy has received extensive attention in the field of monitoring cancer recurrence and metastasis. This approach achieves cancer detection and monitoring by analyzing biomarkers in bodily fluids (such as blood, urine, saliva, pleural effusion, sputum, and cerebrospinal fluid), primarily including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and extracellular vesicles (EVs).^207–209 Compared to traditional tissue biopsy, liquid biopsy offers distinct advantages such as non-invasiveness or minimal invasiveness, lower cost, repeatable sampling, and enhanced sensitivity.²¹⁰ This technology is increasingly recognized as a transformative tool in precision oncology, bridging critical gaps in conventional diagnostic paradigms.²¹¹ However, due to the extremely low abundance of these biomarkers in blood, their detection and isolation remain highly challenging, making the improvement of sensitivity and accuracy a critical issue to be addressed.²¹² GBMs, leveraging their superior electrical conductivity, ultrahigh specific surface area, and tunable surface chemistry, can significantly enhance the sensitivity of liquid biopsy. By efficiently capturing CTCs, enriching ctDNA, and EVs, dynamic and comprehensive tumor dissemination information is provided for the perioperative period, achieving early warning and intervention of recurrence and metastasis.

Efficient Capture of CTCs

GBMs significantly enhance the capture efficiency, detection accuracy, and separation resolution of CTCs, thereby establishing a crucial technological foundation for preoperative assessment of metastasis risk, dynamic postoperative recurrence monitoring, and the development of personalized prognostic treatment strategies. A dual-targeting functionalized rGO film system with enhanced CTC capture efficiency for hepatocellular carcinoma was developed, which improves enumeration accuracy through fluorescence imaging constructed by leveraging the fluorescence quenching properties of rGO, enabling preoperative metastasis assessment.²¹³ In parallel, a GO honeycomb microarray enables single-CTC capture and metastasis potential analysis via synergistic physical confinement/chemical recognition.²¹⁴ Its crosstalk-resistant design supports high-sensitivity liquid biopsy for real-time postoperative metastasis monitoring and recurrence risk assessment. Complementing this, Zhou et al’s graphene-enhanced BIMNs achieve >85% CTC capture efficiency and >94% purity with 98% cell viability, enabling therapeutic efficacy monitoring and metastasis assessment.²¹⁵ For peripheral blood from metastatic castration-resistant prostate cancer (mCRPC), Kozminsky’s GO microfluidic chip captures CTCs/clusters at 3–5 cells/mL with 98% viability and minimal WBC interference, enabling therapy resistance monitoring and metastasis prognosis.²¹⁶ Collectively, these graphene-engineered platforms demonstrate transformative potential in liquid biopsy for precision metastasis surveillance across cancer types.

High-Efficiency Enrichment of ctDNA

GBMs significantly enhance the performance of ctDNA detection, providing crucial technical support for preventing recurrence and metastasis during the perioperative period of cancer, owing to their superconductivity, high specific surface area, and ease of modification. Kong et al developed an argonaute-mediated graphene field-effect transistor that can analyze ctDNA mutations in real time with single-nucleotide resolution within 5 minutes, enabling immediate assessment of residual tumor lesions during surgery.²¹⁷ In ultra-sensitive postoperative tracking, the 3D graphene/gold-platinum-palladium nanoflower sensor by Chen et al (detection limit: 0.13 pM) and the nitrogen-doped graphene-covalent organic framework platform by Guo et al (detection limit: 7.65 fM) use trimetallic catalytic and Prussian blue-mediated signal amplification, respectively, to capture trace amounts of postoperative circulating tumor DNA (ctDNA).^218,219 In addition, Yang et al combined GO-functionalized magnetic beads (MB@GO) with a paper-based microfluidic POCT system, thereby enhancing enrichment efficiency via magnetic enrichment and facilitating the clinical translation of the detection technology.²²⁰ These innovative technologies establish a multi-dimensional barrier to prevent recurrence, aiding in intraoperative decision-making, postoperative recurrence warning, and personalized treatment.

Detection and Isolation of EVs

GBMs can also efficiently separate and detect extracellular vesicles, providing crucial functional supplementary information for perioperative prevention and control of recurrence and metastasis. There are relevant research reports that using the high conductivity, large specific surface area and easy modification characteristics of graphene and its derivatives (such as rGO and GO), combined with the specific recognition of aptamers or antibodies, highly sensitive and unlabeled biosensors have been developed, which have realized the efficient separation and detection of extracellular vesicles (such as exosomes and microcapsules) in TMEs such as liver cancer, colorectal cancer and breast cancer, significantly improved the sensitivity and specificity of early diagnosis, provided more abundant and multi-dimensional biological information and provided potential technical support for real-time monitoring of postoperative cancer treatment and optimization of personalized treatment schemes.^221–223

In summary, leveraging their exceptional intrinsic properties, GBMs enable highly efficient capture of CTCs, enrichment of ctDNA, and isolation of EVs. Through consistent and precise analysis, these materials facilitate dynamic monitoring of cancer recurrence and metastasis throughout the perioperative period. Future advancements will focus on integrating the complementary biological information from CTCs, ctDNA, and EVs. Multi-modality imaging correlated analysis of this integrated data will significantly enhance both the precision and real-time capabilities of perioperative recurrence and metastasis monitoring.

Multifunctional Synergy for Precise Intervention in Cancer Recurrence and Metastasis

Building on the liquid biopsy monitoring outlined in the first section of this chapter, the initial link in the defense chain has been established. The crux of blocking recurrence and metastasis lies in converting warning signals into precise intervention measures. However, current clinical interventions such as adjuvant chemotherapy and radiotherapy often fall short due to off-target toxicity, drug resistance, and their limited impact on cancer stem cells (CSCs) and the immunosuppressive TME. GBMs, endowed with inherent CSC-clearing capabilities, high drug-loading capacity, exceptional photothermal conversion efficiency, and immunomodulatory properties, offer a promising solution. Herein, we propose a “monitoring-intervention” closed-loop strategy leveraging GBMs: through their multifunctional integration, they can achieve three key objectives: (1) efficient clearance of CSCs to eliminate the “seeds” of recurrence; (2) profound remodeling of the TME to dismantle barriers to metastasis; and (3) intelligent delivery of personalized therapeutic vaccines to activate sustained immune surveillance. The synergistic interplay of these three functions not only enables precise eradication of residual lesions but also fosters the formation of a “biological firewall” via immune memory. This approach thus provides an integrated therapeutic solution for early-stage high-risk patients identified through liquid biopsy.

Eliminating CSCs

GBMs effectively eliminate CSCs, targeting the root cause of cancer recurrence and metastasis. Studies confirm that GO itself can eradicate CSCs through differentiation-based nano-therapy, preventing relapse, metastasis, and drug resistance.²²⁴ This GO tablet can also be used as a flushing fluid in the hands during the perioperative period of cancer surgery to remove residual tumor stem cells at the tumor resection site or in the abdominal cavity. Furthermore, GQDs insert into DNA major grooves to downregulate ALDH1/Notch1/MDR1 genes, simultaneously clearing CSCs, inhibiting metastasis, and reversing multidrug resistance at low non-toxic doses.²²⁵ Moreover, functionalized GBMs can be used as drug carriers and can target the treatment to clear CSCs.^226,227 Notably, rGO-silver nanocomposites suppress mammosphere formation and CSC marker genes.²²⁸ Collectively, both intrinsic and functionalized graphene materials eradicate CSCs to block cancer progression fundamentally.

Remodeling TME

GBMs enable multi-dimensional remodeling of the TME to block metastasis. Firstly, GBMs can reprogram tumor-associated macrophages (TAMs) and relieve hypoxia. GO loaded with TLR agonist R848 converts pro-tumor M2-TAMs to anti-tumor M1-type, reversing immunosuppression, enhancing T-cell infiltration, and inhibiting glioma growth.²²⁹ Heparin-modified GO in transdermal systems achieves deep delivery via EPR-like effects and LYVE-1-mediated transport; combined with photothermal therapy, it reverses M2 polarization, relieves hypoxia, activates systemic immunity, and inhibits primary/distal tumors and metastasis.²³⁰ GQDs deliver miR155 to reprogram TAMs,²³¹ while GO-gold nanoparticle composites catalyze oxygen generation to alleviate hypoxia,²³² all providing innovative strategies for precise TME regulation. Secondly, GBMs enable enhanced immunogenic cell death (ICD). GO induces ICD via NIR photothermal effects, releasing “eat-me” signals and synergizing with capsaicin-triggered pyroptosis to drive dendritic cell maturation and T-cell infiltration, establishing long-term immune memory in breast cancer.²³³ Edge-oxidized graphene improves hypoxia, amplifies ICD, activates DC-T cell immunity, and polarizes TAMs to M1, providing advantages for neoadjuvant therapy.²³⁴ GQD/Cu₂O heterojunctions achieve TME-responsive cuproptosis and synergistic therapy, amplifying ICD to reverse immunosuppression.²³⁵ The biomimetic C-GAP platform enhances the immune cell regulatory response caused by radiotherapy through the ROS amplification effect of GBMs, promotes the infiltration of CD8⁺ T cells, and reshapes the TME of oral squamous cell carcinoma.²³⁶ Thirdly, GBMs deliver immune checkpoint inhibitors (eg, PD-1/PD-L1,²³⁷ LILRB4 inhibitors²³⁸) via targeted release. These materials stimulate vascular endothelial cells to disrupt tight junctions, enhance drug/T-cell infiltration, upregulate adhesion molecules, activate DCs, modulate cytokines, and trigger cGAS/STING pathways.²³⁹ This reverses immunosuppression and synergizes with therapies like photothermal treatment to remodel the TME.²⁴⁰ Collectively, these strategies provide innovative approaches for precise TME regulation.

Personalized Cancer Vaccine Carrier / Adjuvant

Functionalized GBMs serve as precision delivery platforms and immunostimulatory adjuvants for personalized cancer vaccines, enabling sustained immune surveillance and intervention. Their high surface area and hydrophobic properties allow efficient antigen loading and targeted slow release. For example, a 3D alginate-rGO scaffold serves as a vaccine carrier, efficiently loading model antigens ovalbumin and granulocyte-macrophage colony-stimulating factor to prolong dendritic cell activation.²⁴¹ Similarly, dextran-modified rGO (rGO-dextran) enhances ovalbumin delivery to DCs, improving MHC-I antigen presentation and increasing pro-inflammatory cytokine (IL-12, TNF-α) secretion versus soluble ovalbumin.²⁴² This induces potent cytotoxic T-cell responses and suppresses tumor growth. Beyond delivery, functionalized graphene materials also serve as novel adjuvants, enhancing the efficacy of traditional adjuvants (eg, alum, AuNPs). Aluminum hydroxide (Alum)-functionalized GO) nanocomposites disrupt lysosomal membranes to promote cytosolic antigen delivery.²⁴³ This combines Alum’s humoral immunity with DC maturation and robust CD8⁺ T-cell activation, significantly inhibiting tumors and supporting tumor-lysate-based personalized vaccines. Furthermore, the dual carrier-adjuvant functionality amplifies cancer immunity. Ultrasmall GO-gold nanoparticle complexes act as a cadjuvant, synergizing dual carrier-adjuvant functions to augment both humoral and cellular immune responses simultaneously.²⁴⁴ Polyethylene glycol-functionalized rGO efficiently targets the lymph node as a carrier, while adjuvant activity induces DC ROS generation to boost antigen presentation.²⁴⁵ A single injection elicits sustained (30-day) neoantigen-specific T-cell responses and tumor suppression. Zhou et al developed an rGO/MTX/SB nanoplatform wherein rGO enables laser-triggered photothermal tumor ablation (58°C) to enhance antigen release, concurrently functions as an immunostimulatory adjuvant, and synergizes with drug-loading capabilities. This integration achieves rGO-mediated photothermal-chemo-immunomodulation, ultimately establishing an “in situ vaccination” effect.²⁴⁶

In summary, GBMs can integrate liquid biopsy for enhanced monitoring of cancer recurrence and metastasis, while simultaneously clearing CSCs, remodeling the TME, and enabling personalized tumor-targeted delivery with adjuvant properties. These capabilities are expected to collectively constitute a precise therapeutic system for perioperative cancer monitoring and intervention (Figure 7). However, as discussed in this section, although “monitoring” and “intervention” are closely interrelated, current research largely remains focused on optimizing them independently. The truly revolutionary potential of GBMs lies in their capacity to function as an all-in-one theranostic platform. Crucially, their ultra-high specific surface area and abundant chemical sites enable the integration of highly sensitive sensing units (for the continuous, real-time monitoring of recurrence-related biomarkers) and on-demand responsive/activatable therapeutic modules (eg, for controlled drug release, photothermal/photodynamic therapy, and immunomodulation) onto a single material. This positions them to construct a dynamic, self-adaptive, closed-loop management platform intelligent enough to span the entire cancer perioperative chain: from preoperative warning and intraoperative navigation/hemostasis to postoperative healing/repair and long-term monitoring/intervention. Recognizing the importance of such a platform in achieving a fundamental breakthrough in cancer surgical cure rates is essential, and it represents the core vision of this review.

Figure 7.

Graphene-Based Monitoring-Therapeutic Integrated System for Perioperative Control of Cancer Metastasis and Recurrence. The system consists of four sequentially connected modules: (A) Monitoring. Liquid biopsy captures CTCs, enriches ctDNA, and detects EVs to achieve early detection of small residual lesions; (B) Warning. Data analysis and risk assessment, issuing warning signals; (C) Intervention. Clearing CSCs, Remodeling TME, and vaccine vector therapy; (D) Feedback. Evaluate the therapeutic effect after the intervention and guide adjustments to subsequent monitoring plans. The arrows between modules indicate the direction of information flow, forming a closed loop of “monitoring warning intervention feedback”. The arrows ↑, ↓, and × in (C) represent elevation, decrease, and inhibition, respectively. As shown in the figure, GBMs generate mild hyperthermia via infrared photothermal effects, which dilate blood vessels in the immunosuppressive tumor microenvironment, increase blood flow rate and oxygen supply, thereby alleviating tumor hypoxia. The content of HIF-1α decreases accordingly thereby inhibiting the production of CD47, PD-L1, and COX-2 and relieving immunosuppression. This figure is adapted from.^{224,241,242,247}

Challenges and Prospects

Challenges and Coping Strategies

Although GBMs have shown broad application prospects in various stages of the perioperative period, their clinical translation still faces several key obstacles. This section will systematically analyze the main challenges faced by the clinical translation of GBMs from the aspects of biosafety, renal clearance, balance between hemostasis and thrombus risk, and regulatory pathways, and explore corresponding solutions.

Biosafety Concerns

The biosafety of GBMs is not an intrinsic, unchangeable property, but rather a tunable variable that depends heavily on physicochemical parameters such as size, dose, and route of exposure.^248,249 Jiang et al reported that the toxicity of GO increases with decreasing size, as smaller GO sheets are more readily internalized and generate higher levels of ROS.²⁵⁰ The toxicity of GBMs also exhibits significant dose-dependence—higher concentrations lead to greater toxicity.²⁵¹ Furthermore, oral administration is poorly absorbed and quickly excreted, with extremely low toxicity; although intraperitoneal injection resulted in long-term accumulation of the material in the liver and spleen, it did not cause significant toxicity, further proving that the exposure pathway determines its toxicity.²⁵² These findings suggest that by regulating dosage, functionalizing modifications, standardizing synthesis methods, and selecting appropriate exposure pathways, the toxicity of GBMs can be effectively reduced, thereby enhancing their biosafety in cancer perioperative applications.^253,254

Renal Clearance

Previous studies have shown that thin, dispersed, and flexible GO nanosheets can cross the glomerular filtration barrier and be excreted in urine without causing significant renal dysfunction.²⁵⁵ Chen et al reported that both small-sized GO (s-GOs) and large-sized GO (l-GOs) can be cleared renally after intravenous injection in mice.²⁵⁶ l-GOs are primarily excreted via proximal tubular secretion, with renal clearance rates significantly higher than those of s-GOs. Multiple renal drug transporters expressed on the basolateral and luminal membranes of renal tubular epithelial cells were found to be involved in the uptake and efflux of GOs. These findings suggest that tuning the lateral size of GO may represent a viable strategy to mitigate renal toxicity.

Balancing Hemostasis and Prothrombotic Risk

While GBMs exhibit excellent hemostatic properties, their prothrombotic potential remains a critical consideration for clinical translation. Previous studies have shown that GO activates platelets through surface charge-mediated Src kinase and calcium signaling pathways, promoting platelet aggregation and granule release, ultimately leading to thrombosis in vivo.¹⁰⁸ In contrast, rGO exhibits significantly lower thrombotic risk due to reduced surface charge, highlighting the key role of surface chemistry in modulating safety profiles. Subsequent studies demonstrated that amine-modified graphene greatly reduces thrombotic risk, showing no platelet stimulation and no pulmonary thrombosis in mice after intravenous injection.²⁵⁷ The abundant oxygen-containing functional groups on GO surfaces enable crosslinking with other functional molecules, mitigating thrombotic risk while enhancing hemostatic function. Chen et al developed a GO-polysaccharide composite hemostatic sponge that achieves rapid hemostasis through the dual actions of physical adsorption and platelet stimulation, exhibiting excellent hemostatic performance.²⁵⁸ Thus, functional modification or composite formation may represent a promising strategy to balance the local hemostatic efficacy and systemic thrombotic risk of GBMs.

Regulatory Complexity

The multifunctional platform attributes of GBMs make them face complex regulatory paths. Due to the fact that the same material system involves multiple functions such as imaging (diagnostic equipment), treatment (drugs), hemostasis (medical devices), drug delivery, biosensing, and tissue regeneration, the GBM platform is likely to be classified as a combination product that needs to meet the approval requirements of multiple regulatory categories, significantly increasing the administrative and technical barriers to clinical translation. To address this challenge, maintaining dialogue with regulatory agencies from the early stages of research and development, clarifying the regulatory classification and approval path of products, establishing a standard characterization and safety assessment system for multifunctional nanomaterial platforms, and promoting international regulatory coordination to reduce uncertainty caused by classification differences in different regions will be key strategies for promoting their clinical translation.

Comparative Selection of GBM Types for Stage-Specific Applications

The above challenges have varying manifestations and impacts at different perioperative stages. Different GBM types also exhibit distinct advantages in functional positioning and applicability at each stage. Table 3 summarizes the commonly used GBM types, selection criteria, key roles, and clinical translation bottlenecks in each stage.

Table 3.

Comparison of GBM Types for Stage-Specific Applications

Perioperative Stage	Most Suitable GBM Type	Selection Rationale	Key Functions and Advantages	Clinical Translation Barriers
Preoperative diagnosis	GQDs	Ultra-small size (<10 nm) for easy clearance, high quantum yield, low toxicity.	High-sensitivity imaging, low toxicity, easy clearance	Targeting specificity, in vivo clearance pathways
Intraoperative navigation	rGO	Enhanced NIR-II absorption after reduction, high photothermal response	Real-time imaging, non-ionizing radiation	Tissue penetration depth, short-term biocompatibility
Hemostasis	GO	Hydrophilic surface, high surface area for physical adsorption, pro-coagulant activity	Physical adsorption combined with coagulation activation for rapid hemostasis	Thrombotic risk, batch-to-batch consistency
Antibacterial/ wound healing	GO	Surface oxidative stress, physical membrane disruption	Multi-mechanism synergy, no drug resistance	Efficacy in immunosuppressive microenvironment
Tissue regeneration	Graphene composite scaffold	Excellent conductivity, adjustable mechanical strength, suitable for tissue regeneration scaffold requirements	Biomimetic structure-guided functional regeneration	Degradability, mechanical matching
Recurrence monitoring	GQDs	High sensitivity via fluorescence quenching recovery, low background interference	High-sensitivity real-time detection	Clinical sample validation, device integration
Recurrence intervention	GO	High surface area for drug/gene loading, facile functionalization	Targeted delivery, immune microenvironment remodeling	Targeting efficiency, long-term safety

Notes: The selection rationale for each GBM type is based on its key physicochemical properties (eg, size effects, surface chemistry, conductivity, photothermal performance). The conclusions in this table are drawn from the discussions in the main text; detailed references can be found in the corresponding chapters.

From Table 3, it can be seen that GO has been widely used in various stages such as diagnosis, hemostasis, and antibacterial due to its rich surface chemistry and good dispersibility; RGO is more suitable for intraoperative navigation and electroactive tissue engineering due to its improved conductivity and photothermal properties after reduction; GQDs have unique advantages in imaging and sensing fields due to their size effect and fluorescence properties; Graphene has irreplaceable value in tissue regeneration due to its ultra-high conductivity and excellent mechanical strength. However, a single GBM type is unlikely to cover all perioperative stages, and each stage faces varying degrees of clinical-translational barriers. This suggests that future material design needs to seek a balance between functional integration and process simplification.

In summary, the challenges discussed above are not insurmountable. Through rational material design, surface functionalization, size optimization, and early regulatory engagement, these obstacles can be systematically addressed. These strategies provide a foundation for moving GBMs from laboratory research toward clinical application.

Future Directions

In addition to the above strategies, the long-term development of GBM platforms also requires a broader perspective. In the future, we should focus on the following directions.

Firstly, graphene-based platforms are evolving towards integrated closed-loop systems that incorporate real-time sensing, intelligent response, and active intervention. This type of system is expected to continuously monitor postoperative circulating tumor markers and trigger local treatment as needed when risk signals are detected, such as photothermal ablation or controlled drug release, thereby transforming passive monitoring into active intervention.

Secondly, a deeper understanding of how the physical signals of graphene regulate cell behavior, including migration, proliferation, differentiation, and microenvironment remodeling, will provide guidance for the design of intelligent dressings and scaffolds. This type of material can sense changes in the wound microenvironment (such as pH, enzymes, reactive oxygen species, etc.) and adaptively release therapeutic signals, thereby promoting vascularization, neurogenesis, and in situ tissue regeneration, ultimately achieving functional tissue reconstruction after cancer surgery.

Thirdly, combining GBMs with artificial intelligence and intraoperative multimodal imaging is expected to advance the development of next-generation surgical navigation systems. Artificial intelligence has achieved sub-10-second real-time feedback on tumor infiltration in cancer surgery.⁷³ By combining AI-driven predictive models with GBM imaging probes and liquid biopsy data, this approach is expected to establish a surgical navigation system with real-time risk prediction and decision support, thereby improving the accuracy and safety of surgery.

Overall, these directions will drive the GBM platform from concept validation to clinical practice, providing transformative solutions for perioperative cancer management.

Conclusion

This review systematically summarizes the application progress of GBMs across various stages of perioperative cancer management and, for the first time, proposes GBMs as a unified platform for closed-loop management throughout the perioperative cancer phase. GBMs, with their inherent multifunctionality, precise programmability, and physicochemical properties as functional bridges, have the potential to span the perioperative pathway from preoperative diagnosis to long-term recurrence monitoring and intervention, promoting a paradigm shift in perioperative treatment from a passive response to complications to active, intelligent, and closed-loop management.

Although GBMs have shown broad application potential across various stages of the perioperative period, their clinical translation still faces multiple challenges, including biosafety, renal clearance, hemostasis and thrombus balance, and regulatory pathways. Through rational material design, a standardized safety assessment system, and early regulatory communication, these obstacles are expected to be gradually overcome. With the ongoing development of intelligent response systems, AI-assisted navigation, and interdisciplinary collaboration, GBMs are expected to move from laboratory research to clinical practice, providing transformative solutions for perioperative cancer management.

Data Sharing Statement

No datasets were generated or analysed during the current study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare no conflicts of interest in this work.