Recent advances in biomaterials for osteosarcoma treatment

Abstract

Osteosarcoma is a highly aggressive bone malignancy with poor prognosis due to high metastasis and drug resistance. Conventional treatments often result in systemic toxicity and limited efficacy, highlighting the need for more precise and integrative approaches. Biomaterials with excellent biocompatibility and functional tunability have emerged as promising tools to enhance local therapy and support bone regeneration. This review summarizes recent advances in the application of natural, synthetic and composite biomaterials in four key areas: drug delivery, gene therapy, immunotherapy and post-resection bone repair. To provide a systematic perspective, we compiled and classified 64 representative studies published between 2021 and 2025, comparing biomaterial-based delivery strategies ranging from single-material carriers to multifunctional composite platforms. Particular focus is given to stimuli-responsive systems and scaffolds that integrate antitumor activity with regenerative capacity. By outlining emerging strategies and material platforms, this review offers a concise reference for the rational design of biomaterials addressing the dual challenge of tumor eradication and skeletal reconstruction. Interdisciplinary collaboration will be key to advancing these systems toward clinical application.

Graphical abstract

Introduction

Osteosarcoma is the most common primary malignant bone tumor, characterized by the production of osteoid matrix by neoplastic cells [1]. It predominantly affects children, adolescents and young adults, with a peak incidence during the adolescent growth spurt [2]. Despite its relative rarity, accounting for less than 1% of all cancers diagnosed annually in the United States, osteosarcoma represents a significant challenge in pediatric oncology [1, 3]. The incidence is slightly higher in males than females, with approximately 1000 new cases diagnosed each year in the United States, of which about 500 occur in individuals under 20 years of age [1, 4].

The current standard of care for osteosarcoma involves a multimodal approach combining surgery, systemic chemotherapy, and in some cases, radiation therapy [5]. While this treatment paradigm has dramatically improved outcomes since its introduction, with 5-year survival rates increasing from less than 20% in the 1970s to 60–70% for patients with localized disease, significant challenges remain [1, 6]. For patients presenting with metastatic disease at diagnosis (approximately 15–20%), the prognosis remains poor, with 5-year survival rates as low as 19% [7]. Moreover, 30–40% of patients with initially localized disease will experience recurrence, further highlighting the limitations of current therapeutic approaches [8, 9]. The mainstay of systemic therapy for osteosarcoma relies on a combination of high-dose methotrexate, doxorubicin (DOX) and cisplatin [10]. However, this intensive chemotherapy regimen is associated with significant toxicities, including myelosuppression, cardiotoxicity and nephrotoxicity [11]. Furthermore, the development of drug resistance remains a major obstacle in improving outcomes for patients with recurrent or metastatic disease [12]. These challenges underscore the urgent need for novel therapeutic strategies that can enhance efficacy while minimizing toxicity.

In recent years, biomaterials have emerged as a promising avenue for improving cancer therapy, including the treatment of osteosarcoma [13]. Biomaterials are synthetic or naturally derived substances designed to interact with biological systems for therapeutic or diagnostic purposes [14, 15]. Their unique properties, including biocompatibility, biodegradability and the ability to be functionalized for specific applications, make them ideal candidates for developing advanced drug delivery systems and tissue engineering scaffolds [16, 17].

The application of biomaterials in osteosarcoma treatment offers several potential advantages [18]. First, they can serve as carriers for targeted drug delivery, potentially increasing the concentration of therapeutic agents at the tumor site while reducing systemic toxicity [19]. Second, biomaterials can be engineered to provide controlled and sustained release of drugs, potentially overcoming issues of drug resistance and improving treatment efficacy [20]. Third, in the context of bone tumors, biomaterials can be designed to mimic the extracellular matrix, potentially aiding in bone regeneration following tumor resection [21].

Moreover, the versatility of biomaterials allows for the development of multifunctional platforms that can combine therapeutic delivery with diagnostic capabilities, paving the way for personalized treatment approaches [22]. As research in this field progresses, biomaterials are increasingly being explored for their potential to enhance immunotherapy, facilitate gene therapy and improve the efficacy of conventional chemotherapeutic agents in the treatment of osteosarcoma [20, 23].

This review aims to provide a comprehensive yet focused synthesis of recent progress in biomaterials specifically developed for osteosarcoma treatment. Rather than presenting a general survey of materials for orthopedic or bone repair, we highlight emerging biomaterial strategies uniquely tailored to the complex pathophysiology of osteosarcoma, including multifunctional platforms that integrate antitumor efficacy with bone regeneration, tumor-responsive release systems and immune-modulatory delivery technologies.

We examine advances across multiple therapeutic dimensions, including drug delivery, gene therapy, immunotherapy and post-resection regenerative scaffolds, offering an integrative framework for future translational development. While this review does not aim to be exhaustive, it focuses on representative studies published since 2021, identified through targeted searches in PubMed using terms such as “osteosarcoma,” “biomaterials,” and “bone regeneration.” Priority was given to novel or multifunctional strategies relevant to both tumor inhibition and bone tissue engineering. Reference lists of relevant articles were also consulted to capture key developments.

Types of biomaterials used in osteosarcoma treatment

The field of biomaterials for osteosarcoma treatment has witnessed significant advancements in recent years, moving beyond traditional materials to encompass a diverse array of innovative solutions. These biomaterials play crucial roles in addressing the complex challenges associated with osteosarcoma, including tumor resection, bone reconstruction and targeted drug delivery. This comprehensive review explores the three main categories of biomaterials used in osteosarcoma treatment: natural biomaterials, synthetic biomaterials and innovative composite biomaterials (Figure 1).

Figure 1.

Schematic overview of key biomaterial categories for osteosarcoma treatment. The figure categorizes biomaterials into three major types: natural, synthetic and composite and illustrates their structural characteristics, functional properties and biomedical applications. (A) Natural biomaterials (left), including collagen, chitosan and silk fibroin, exhibit excellent biocompatibility and bioactivity, mimicking the ECM of bone while enabling controlled drug release and tumor microenvironment modulation through pH responsiveness and ROS generation. (B) Synthetic biomaterials (right), such as PLGA, PCL and MSNs, offer precise engineering flexibility, enabling multidrug encapsulation, targeted delivery and spatiotemporal release through polymer degradation or surface modification strategies. (C) Composite biomaterials (bottom), including Col-HA and GelMA-HA, combine the biological functionality of natural polymers with the mechanical tunability and delivery performance of synthetic scaffolds. These systems are often used in 3D printing and post-resection bone implantation. These platforms represent a multifunctional biomaterial toolkit for osteosarcoma management, integrating antitumor delivery with regenerative capabilities. Created with BioRender.com.

Natural biomaterials: harnessing bioactivity

Natural biomaterials have gained considerable attention in osteosarcoma treatment due to their inherent bioactivity, biocompatibility and ability to mimic the extracellular matrix (ECM) of bone tissue [13, 24, 25]. These materials offer significant advantages in terms of reducing immune response and enhancing integration with the surrounding bone tissue [26, 27].

Collagen, a primary component of the bone ECM, has been extensively studied for its potential in osteosarcoma treatment [28, 29]. Recent research has demonstrated its efficacy in promoting bone cell proliferation and improving the overall biocompatibility of scaffolds [30, 31]. Studies demonstrated that collagen-I coating of titanium and steel implants via cold low-pressure gas plasma treatment improved biocompatibility [32, 33]. This technique resulted in increased cell viability and attachment rates of osteoblast-like osteosarcoma cells, which could have implications for improving implant integration in osteosarcoma patients. The natural structure of collagen fibers provides an ideal environment for osteoblast attachment and growth, facilitating the regeneration of healthy bone tissue [34, 35]. Gelatin, a denatured form of collagen, has also shown promise in osteosarcoma treatment strategies [36].

Silk fibroin has emerged as a promising material for drug delivery systems in osteosarcoma treatment due to its exceptional properties and versatility [37]. Silk fibroin-based delivery systems have demonstrated remarkable efficacy in targeting and killing tumor cells while minimizing side effects and drug resistance, a crucial factor in improving cancer treatment outcomes [38, 39]. One of the key advantages of silk fibroin is its ability to provide sustained and controlled release of anticancer drugs, which is particularly beneficial for the long-term treatment of osteosarcoma [40]. This material’s versatility allows for the delivery of a wide range of therapeutic molecules, including chemotherapeutics, nucleic acid-based therapies, natural-derived agents, therapeutic proteins or peptides, inorganic compounds and photosensitive molecules [41–43]. Silk fibroin can be formulated into nanoparticles, enhancing drug efficacy through modifications in particle size, chemical composition and properties [44]. Furthermore, these nanoparticles can be functionalized with targeting ligands to improve their specificity for cancer cells, as demonstrated in studies using cyclic RGD peptides to target specific integrin receptors overexpressed in certain cancer types [38, 45, 46].

Chitosan, a versatile biopolymer, has emerged as a promising material in osteosarcoma treatment research, particularly in the development of advanced drug delivery systems [47]. Its ability to form nanoparticles has been extensively studied for encapsulating many therapeutic agents, including chemotherapy drugs and siRNA, offering controlled and sustained release profiles [48]. Research has demonstrated the efficacy of chitosan nanoparticles in delivering siRNA to silence cancer-associated proteins and induce apoptosis in osteosarcoma cells [49, 50]. Additionally, copper-loaded chitosan nanoparticles have shown enhanced anticancer effects through improved cellular internalization and increased reactive oxygen species (ROS) generation [51, 52]. The mechanisms underlying chitosan’s efficacy include enhanced cellular uptake, ROS generation and apoptosis induction in cancer cells [53, 54]. Additionally, chitosan nanoparticles have been found to upregulate ROS generation in bone tumor cells, resulting in mitochondrial dysfunction due to reduced membrane potential [55]. This mitochondrial disruption is a key factor in triggering the apoptotic cascade. Moreover, the ability of chitosan nanoparticles to deliver siRNA effectively allows for targeted silencing of cancer-associated proteins, potentially disrupting multiple oncogenic pathways simultaneously [56]. One notable feature of chitosan-based systems is their pH-responsive nature, allowing accelerated drug release in the acidic tumor microenvironment [57]. The pH-responsive nature of chitosan-based systems not only facilitates drug release in the acidic tumor microenvironment but may also contribute to the disruption of tumor cell homeostasis, further enhancing their therapeutic efficacy [58, 59].

A key insight into the use of natural biomaterials in osteosarcoma treatment is their role in reducing immune response and enhancing integration with bone tissue. The structural similarity of these materials to the native ECM helps minimize foreign body reactions, promoting better acceptance of implants and scaffolds by the host tissue. This improved integration is crucial for successful bone regeneration and long-term treatment outcomes in osteosarcoma patients.

Synthetic biomaterials: engineering precision for targeted treatment

Synthetic biomaterials offer unparalleled control over material properties, allowing for precise engineering of scaffolds and drug delivery systems tailored to the specific needs of osteosarcoma treatment [60, 61]. These materials provide a platform for customized release profiles of therapeutic agents and can be designed to offer optimal mechanical support for bone regeneration.

Poly (lactic-co-glycolic acid) (PLGA) has emerged as a versatile and promising biomaterial in osteosarcoma treatment, offering significant advantages in drug delivery and scaffold development [62, 63]. Its biocompatibility, biodegradability and ability to form nanoparticles make it an ideal candidate for developing advanced therapeutic strategies [64]. In nanoparticle-based systems, PLGA can encapsulate a wide range of therapeutic agents, including chemotherapy drugs and small molecules, and can be designed for co-delivery of multiple drugs to enhance therapeutic efficacy [65]. These nanoparticles can be further functionalized with targeting ligands to improve tumor-specific delivery [66]. For targeted photodynamic therapy, PLGA nanoparticles can encapsulate photosensitizers and incorporate targeting moieties, allowing for selective accumulation in tumor cells and more effective localized therapy upon light activation [67, 68]. In postsurgical treatment, PLGA-based 3D printed scaffolds provide structural support for bone regeneration while serving as a platform for local drug delivery [23]. The mechanisms of action of PLGA-based systems are multifaceted, including enhanced drug efficacy through improved bioavailability and cellular uptake, increased ROS generation in photodynamic therapy applications, mitochondrial targeting to disrupt cellular energy production, ferroptosis induction and sustained local drug release [69, 70]. These diverse mechanisms make PLGA-based systems highly versatile and effective in osteosarcoma treatment, offering the potential for improved therapeutic outcomes and reduced side effects compared to conventional approaches [71]. The mechanisms of action of PLGA-based systems include enhanced drug efficacy, increased ROS generation, mitochondrial targeting, ferroptosis induction and sustained local drug release. These properties allow PLGA to improve the delivery and efficacy of chemotherapeutic agents, overcome drug resistance mechanisms and maintain therapeutic concentrations at the tumor site while minimizing systemic side effects.

Polycaprolactone (PCL) is another synthetic polymer that is a biodegradable polyester with excellent biocompatibility and mechanical properties, making it an ideal candidate for developing advanced therapeutic strategies in osteosarcoma treatment [72]. Its primary functions include serving as a drug delivery vehicle and a scaffold material for tissue engineering applications [73]. In drug delivery applications, PCL can be formulated into nanoparticles or microparticles to encapsulate various therapeutic agents [74]. These PCL-based delivery systems offer controlled and sustained release of drugs, potentially improving the efficacy of chemotherapy while reducing systemic side effects [75]. For instance, a study explored the use of PCL nanoparticles for delivering peptides, demonstrating the potential for enhanced drug biodistribution in targeted therapies [76]. As a scaffold material, PCL plays a crucial role in tissue engineering approaches for bone regeneration following osteosarcoma resection [77]. PCL scaffolds provide a structural framework that supports cell growth and differentiation while allowing for the controlled release of therapeutic agents. A notable example is the development of 3D-printed magnesium-PCL scaffolds loaded with melatonin for osteosarcoma treatment [78]. This innovative approach not only provided structural support but also actively inhibited osteosarcoma development by regulating cell-in-cell structures. An additional benefit of PCL in osteosarcoma treatment is its potential for antibacterial properties when combined with other materials. A study demonstrated enhanced antibacterial ability of electro spun PCL scaffolds incorporating ZnO nanowires [79]. This property could be particularly valuable in preventing postsurgical infections in osteosarcoma patients undergoing limb-salvage procedures.

Mesoporous silica nanoparticles (MSNs) represent a class of synthetic biomaterials that have shown great potential in improving the stability and delivery of therapeutic agents for osteosarcoma treatment [80]. Their high surface area and tunable pore size allow for efficient loading of drugs and controlled release profiles [81]. Recent research has demonstrated the efficacy of MSNs in delivering photosensitizers like indocyanine green (ICG) for photothermal therapy in osteosarcoma treatment, showcasing their versatility in advanced treatment modalities [82]. MSNs can be functionalized with targeting ligands to improve their uptake by osteosarcoma cells [83]. MSNs can be designed to overcome drug resistance mechanisms in osteosarcoma cells by co-delivering chemosensitizers or targeting specific resistance pathways. A study developed MSNs loaded with DOX and conjugated with a selenium to overcome multidrug resistance in osteosarcoma cells [84]. MSNs can be engineered to alter the tumor microenvironment, potentially enhancing the efficacy of other treatments. This approach enhanced the efficacy of subsequent radiotherapy. Unlike many materials that can only function therapeutically, MSNs can also be functionalized for diagnostic applications in osteosarcoma [85]. A study created multifunctional MSNs loaded with DOX and gadolinium for simultaneous MRI imaging and chemotherapy of osteosarcoma [85]. This system demonstrated enhanced tumor accumulation and antitumor efficacy while providing real-time imaging capabilities.

A standout feature of synthetic biomaterials in osteosarcoma treatment is their tunability for controlled drug release and bone support. The ability to precisely engineer the physical and chemical properties of these materials allows for the development of sophisticated drug delivery systems with customized release profiles. This level of control is particularly valuable in osteosarcoma treatment, where maintaining therapeutic drug concentrations at the tumor site while minimizing systemic exposure is crucial.

Innovative composite biomaterials: synergizing for enhanced functionality

In osteosarcoma treatment, the integration of natural biomaterials and synthetic biomaterials into innovative composite biomaterials has emerged as a promising approach, offering significant advantages over their individual counterparts [21]. These composite materials exhibit enhanced biocompatibility, improved mechanical properties and superior drug delivery capabilities, addressing the limitations of single-component systems [86]. By combining the bioactivity and cell-friendly nature of natural biomaterials with the tailorable properties and stability of synthetic biomaterials, these innovative composites provide a versatile platform for targeted drug delivery, sustained release of therapeutic agents and promotion of bone regeneration.

Collagen-hydroxyapatite (COLL-HA) composites are designed to mimic the natural composition of bone, typically consisting of collagen and hydroxyapatite (HAp) in ratios similar to that of bone tissue [87]. The incorporation of collagen provides a biocompatible matrix, while HAp contributes to the mechanical strength and osteoconductive of the composite. COLL-HA composites have been investigated as drug delivery systems for the locoregional treatment of bone cancer, particularly osteosarcoma. Researchers have developed COLL-HA composites loaded with cisplatin, a common chemotherapeutic agent [88, 89]. These systems demonstrated cytotoxic, antiproliferative and anti-invasive activities against G292 osteosarcoma cells in vitro. Another research developed a porous COLL-HA scaffolds containing drug-loaded Adriamycin (ADM)-encapsulated PLGA nanoparticles have been explored for osteosarcoma treatment, and exhibited excellent extended-release drug properties, bone repairing and antineoplastic efficacy [90].

In addition to its common combination with collagen, HAp can be blended with a variety of other bioactive substances to create innovative and multifunctional composite biomaterials for osteosarcoma treatment [91]. These diverse composites not only enhance the mechanical and biological properties of the materials but also introduce unique therapeutic benefits. One innovative approach involves selenium-loaded HAp nanoparticles, which have shown both anticancer and osteogenic properties by effectively inhibiting the activity and invasiveness of osteosarcoma cells while promoting the viability and mineralization of bone marrow stem cells [92]. In vivo studies demonstrated a significant reduction in tumor growth in mouse models, indicating their potential as a direct treatment option that activates apoptotic pathways in tumor cells. Another promising development is a bioinspired hydrogel enriched with calcium ions that forms a dense HAp layer, selectively targeting and killing osteosarcoma cells while sparing normal cells, thereby addressing issues like multidrug resistance associated with conventional chemotherapy [93, 94]. Additionally, HAp combined with bovine serum albumin and paclitaxel has been formulated into nanoparticles aimed at postsurgical treatment, inhibiting osteosarcoma cell proliferation and invasion while promoting osteogenic differentiation, making them suitable for adjuvant therapy after surgery [95]. Furthermore, bismuth/strontium/HAp/chitosan composites have been developed to exhibit antitumor, antibacterial and osteogenic properties, enhancing effectiveness against osteosarcoma cells while also providing antibacterial benefits to mitigate infection risks following surgical interventions [96]. Overall, HAp-containing composites represent a promising area of research in the direct treatment of osteosarcoma, demonstrating capabilities that not only support bone regeneration but also actively inhibit tumor growth and enhance healing processes postsurgery. As research advances, these innovative composites may lead to improved therapeutic strategies for managing osteosarcoma effectively.

Gelatin methacryloyl (GelMA) is a versatile and biocompatible hydrogel derived from gelatin that has gained significant attention in tissue engineering and regenerative medicine [97]. It is created by modifying gelatin with methacrylic anhydride, introducing methacrylate groups that allow for photo-crosslinking [98]. GelMA hydrogels offer tunable mechanical properties, excellent biocompatibility and the ability to promote cell adhesion due to retained RGD motifs [99, 100]. GelMA hydrogels are very special in the treatment of osteosarcoma, because in addition to their wide range of direct use as treatment, GelMA hydrogels occupy a very key position in the research stage of osteosarcoma treatment, providing a valuable tool for understanding the disease and developing new treatment strategies. GelMA hydrogels enable the creation of more physiologically relevant 3D osteosarcoma models [101]. These models enable more accurate drug screening, facilitate studies on metastasis and mechanobiology and support the development of personalized medicine approaches. GelMA-based 3D cultures allow researchers to study complex cell-cell interactions, tumor heterogeneity and cell–matrix interactions in a more realistic microenvironment [102, 103]. They serve as effective platforms for high-throughput drug screening, metastasis studies and investigation of mechanotransduction in osteosarcoma cells. Additionally, GelMA hydrogels support the creation of patient-specific models and the study of combination therapies, including multidrug delivery and chemo-radiotherapy models. As research techniques continue to evolve, GelMA-based models are likely to become increasingly important in uncovering new insights into osteosarcoma biology and developing more effective treatment strategies.

With these capabilities, composite biomaterials allow the development of multifunctional treatment modalities that not only suppress tumor growth and facilitate bone repair but also help minimize systemic side effects [104]. Their synergistic design makes them well-suited for personalized, localized and sustained therapies, reinforcing their promise in transforming current osteosarcoma treatment paradigms. Overall, the field of biomaterials for osteosarcoma treatment has evolved significantly, embracing a diverse array of natural, synthetic and composite materials. Natural biomaterials offer excellent biocompatibility and bioactivity, synthetic materials provide precision and tunability, and composite biomaterials synergize these advantages for enhanced functionality. As research in this field continues to advance, the development of increasingly sophisticated biomaterials promises to revolutionize osteosarcoma treatment, offering new hope for improved patient outcomes and quality of life (Table 1).

Table 1.

Comparative summary of representative biomaterial platforms for osteosarcoma treatment.

Biomaterial	Physicochemical properties	Typical therapeutic payloads	In vivo efficacy
Collagen	Biocompatible; ECM mimic; low mechanical strength	Cisplatin, DOX	Promotes osteoblast adhesion; supports osteogenesis
Gelatin	Derived from collagen; biodegradable; cell-adhesive	Various chemotherapeutics	Enhances scaffold biocompatibility; supports tissue integration
Silk Fibroin	Biodegradable; tunable drug release; nanoparticle-compatible	Chemotherapeutics, siRNA, peptides	Sustained release; reduced resistance; improved targeting
Chitosan	Cationic; pH-responsive; forms nanoparticles	siRNA, DOX, Cu2+	Induces ROS; triggers apoptosis; gene delivery capability
PLGA	Biodegradable; tunable degradation rate; nanoparticle-friendly	DOX, methotrexate, photosensitizers	Controlled local drug release; improved bioavailability
PCL	Biodegradable polyester; strong mechanical properties; 3D printable	Melatonin, peptides	Supports bone regeneration; antibacterial when modified
MSNs	High surface area; tunable pores; surface-functionalizability	DOX, selenium, ICG	Combines therapy and imaging; overcomes drug resistance
COLL-HA	Bone-mimetic; osteoconductive composite	Cisplatin, DOX-PLGA NPs	Promotes bone regeneration and tumor suppression
GelMA	Photo-crosslinkable hydrogel; tunable stiffness; RGD motifs	PEDF gene, multiple antitumor drugs	Enables 3D tumor modeling; sustained gene and drug delivery

Biomaterial-based delivery systems for osteosarcoma treatment

Despite advances in treatment modalities, the high metastatic potential, recurrence rates and development of drug resistance in osteosarcoma continue to pose significant challenges. To address these issues, biomaterial-based delivery systems have emerged as promising approaches for enhancing therapeutic efficacy while minimizing adverse effects in osteosarcoma treatment. These systems can be broadly categorized into drug delivery systems, gene delivery systems and immunotherapy and vaccination delivery systems (Figure 2).

Figure 2.

Schematic overview of biomaterial-based delivery systems for osteosarcoma treatment. Biomaterial-based delivery platforms can be broadly categorized into drug delivery, gene delivery and immunotherapy/vaccine delivery systems, with increasing interest in multifunctional co-delivery strategies that occupy the intersection of these domains. (A) Drug delivery systems utilize lipid- or polymer-based nanoparticles, microneedles and hydrogel matrices to enable controlled and localized release of chemotherapeutic agents. (B) Gene delivery systems employ vectors such as nanoparticles, liposomes or bioceramics to deliver DNA, siRNA or miRNA for tumor suppression or gene silencing. (C) Immunotherapy delivery platforms include leukocyte-mimetic nanoparticles, injectable hydrogels and vaccine-loaded carriers to activate antitumor immune responses through checkpoint modulation or antigen presentation. Co-delivery strategies (center) leverage combinatorial effects, for instance, synchronizing chemotherapy with gene silencing or immune activation, to overcome drug resistance and enhance therapeutic efficacy. These integrated platforms reflect a growing trend toward synergistic biomaterial systems capable of addressing multiple therapeutic targets in osteosarcoma. Created with BioRender.com.

Drug delivery systems

Drug delivery systems for osteosarcoma treatment have seen significant advancements in recent years, leveraging various biomaterials to improve the efficacy and safety of chemotherapeutic agents [105]. These systems aim to overcome limitations associated with conventional drug administration, such as poor bioavailability, rapid clearance and off-target toxicity (Figure 3) [47].

Figure 3.

Overview of advanced biomaterial-based drug delivery strategies for osteosarcoma. This figure illustrates the key components and mechanisms involved in the design and function of biomaterial-assisted drug delivery systems. (A) Various nanomaterials and bioceramics carriers, including liposomes, solid lipid nanoparticles, PLGA-based nanoparticles, hydroxyapatite bioceramics and magnetic nanoparticles, are employed as delivery platforms to encapsulate and protect therapeutic agents while enabling tunable release profiles. (B) Two administration routes are shown: systemic delivery (e.g. intravenous infusion), which allows broad distribution but often results in off-target effects, and localized delivery, which involves direct injection at the tumor site, enabling higher local concentrations and reduced systemic toxicity. (C) Stimuli-responsive drug release strategies are increasingly used to improve therapeutic specificity. These include materials engineered to respond to tumor-associated triggers such as acidic pH, oxidative stress, overexpressed enzymes or exogenous cues like light and heat. Upon sensing these stimuli, carrier systems undergo structural changes (e.g. membrane destabilization, matrix degradation), facilitating site-specific drug release within the tumor microenvironment. Created with BioRender.com.

Calcium phosphate-based bioceramics, particularly HAp composites, have demonstrated potential as carriers for antitumor drugs like DOX, cisplatin and gemcitabine [106]. The similarity of HAp to natural bone mineral makes it an excellent candidate for targeted delivery to bone tumors [13]. Moreover, HAp scaffolds combined with magnetic nanoparticles (MNPs) offer the possibility of local magnetic hyperthermia treatment, enhancing the overall therapeutic effect [107]. This combination approach allows for both drug delivery and thermal ablation of tumor cells, potentially improving treatment outcomes. Biodegradable polymers, especially those based on lactic acid, have shown potential as alternatives to metallic implants in bone implant technology, offering a dual function of drug delivery and structural support [108]. PLGA and PCL are commonly used polymers in this context. These polymeric systems can be engineered to provide controlled release of chemotherapeutic agents, potentially overcoming drug resistance mechanisms and reducing systemic toxicity [23]. The degradation rate of these polymers can be tuned to match the desired drug release profile and bone regeneration timeline. Lipid-based nanoparticles and liposomal formulations have been extensively explored for their ability to improve drug solubility and enhance targeted delivery to osteosarcoma sites [109]. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) offer advantages such as high drug loading capacity, improved stability and the ability to incorporate both hydrophilic and hydrophobic drugs [110]. Liposomal formulations, particularly those incorporating polyethylene glycol (PEG) for “stealth” properties, have shown improved pharmacokinetics and reduced systemic toxicity in osteosarcoma models [23, 109].

The development of stimuli-responsive drug delivery systems has further expanded the possibilities for controlled and targeted drug release in osteosarcoma treatment [111]. pH-sensitive nanoparticles and hydrogels have been designed to trigger drug release in the acidic tumor microenvironment, potentially enhancing therapeutic efficacy while minimizing off-target effects [112]. This approach takes advantage of the lower pH typically found in tumor tissues compared to normal tissues. Thermosensitive systems, such as certain polymeric nanoparticles and liposomes, can be triggered to release their payload in response to local hyperthermia, allowing for precise spatial and temporal control of drug delivery [113]. This strategy can be particularly useful when combined with other treatment modalities like radiation therapy or focused ultrasound [114]. Recent advancements in nanotechnology have led to the development of multifunctional nanoparticles that combine diagnostic and therapeutic capabilities, known as theranostic nanoparticles. For instance, iron oxide nanoparticles functionalized with chemotherapeutic drugs can serve as both MRI contrast agents and drug delivery vehicles, enabling real-time monitoring of drug distribution and tumor response [85].

In brief, recent advancements in drug delivery systems for osteosarcoma treatment utilize biomaterials, polymers and nanotechnology to improve targeted delivery and controlled drug release. These innovations aim to enhance therapeutic efficacy, minimize toxicity and integrate diagnostic and therapeutic capabilities.

Gene delivery systems

Gene therapy holds significant promise for osteosarcoma treatment, offering the potential to target specific genetic alterations associated with tumor growth and progression [115]. However, effective delivery of genetic material to tumor cells remains a critical challenge. Biomaterial-based gene delivery systems have been developed to address this issue, providing protection for nucleic acids and facilitating their cellular uptake and intracellular release [116].

Microneedle-guided delivery systems have emerged as an innovative approach for gene therapy in osteosarcoma (Figure 4) [117]. Dissolving microneedles (dMN) based on biocompatible amphiphilic tri-block copolymers enable the self-assembly of nano-micelles containing hydrophobic drugs or genetic material [118]. This system has shown potential for delivering gene-based therapies to skin tumors and osteosarcoma, offering a minimally invasive approach for localized gene delivery. Targeted drug delivery for osteosarcoma treatment, showing nanoparticles entering tumor cells, releasing chemotherapeutic agents, damaging DNA and RNA and ultimately inducing apoptosis to eliminate the osteosarcoma cells [119].

Figure 4.

Schematic illustration of microneedle‐based gene therapy for osteosarcoma. This figure depicts the localized delivery of gene- or drug-loaded nanoparticles using MN platforms for targeted osteosarcoma treatment. The nanoparticles encapsulated within liposomes, polymeric or lipid-based carriers are incorporated into four functional microneedle designs: (A) Solid MNs create microchannels in the skin to facilitate passive nanoparticle diffusion; (B) Coated MNs deliver therapeutic agents via surface-loaded cargo that dissolves rapidly upon insertion; (C) Dissolvable MNs are fully biodegradable, releasing their entire payload as the needle matrix dissolves; (D) Hollow MNs actively inject nanoparticle suspensions through internal lumens. Once delivered, the nanoparticles penetrate tumor cells, enabling gene regulation (e.g. silencing oncogenes or delivering tumor-suppressor genes) and promoting apoptosis through transcriptional disruption or toxin induction. This approach enables minimally invasive, localized and efficient nucleic acid delivery directly to bone tumor sites, reducing systemic toxicity and improving therapeutic precision. Created with BioRender.com.

Hydrogel-based systems have also demonstrated promise for gene delivery in osteosarcoma treatment [120]. A notable example of hydrogel use in gene therapy for osteosarcoma treatment involves a chitosan-based hydrogel system designed to deliver the pigment epithelium-derived factor (PEDF) gene [121]. This in situ gelling system forms at the application site, allowing for localized and sustained release of the therapeutic gene. The hydrogel’s key features include controlled release of the PEDF gene, targeted delivery to the tumor site, potential for combination with conventional chemotherapy, and minimally invasive application. This approach demonstrates how hydrogels can serve as versatile platforms for gene therapy in osteosarcoma treatment, offering precise delivery and the potential for enhanced therapeutic efficacy.

Nanoparticle-based systems, including lipid and polymer-based nanocarriers, have been extensively studied for gene delivery in osteosarcoma. These systems can protect nucleic acids from degradation, facilitate cellular uptake and enable targeted delivery to tumor sites [122]. Cationic lipid nanoparticles, for example, have shown efficacy in delivering siRNA and miRNA for gene silencing in osteosarcoma models [123, 124]. Polymer-based nanocarriers, such as those based on polyethyleneimine (PEI) or poly(amidoamine) (PAMAM) dendrimers, have also demonstrated potential for efficient gene transfection in osteosarcoma cells [13].

Gene therapy for osteosarcoma offers promising strategies to target tumor-specific genetic alterations, with advancements in biomaterial-based delivery systems like microneedles, hydrogels and nanoparticles enabling effective and localized gene delivery. These systems enhance therapeutic efficacy by protecting genetic material, facilitating targeted delivery and offering minimally invasive application methods.

Immunotherapy and vaccination delivery systems

Immunotherapy has emerged as a promising approach for osteosarcoma treatment, aiming to harness the power of the immune system to combat cancer cells. Biomaterial-based delivery systems play a crucial role in enhancing the efficacy of immunotherapeutic agents and vaccines by providing controlled release, protection from degradation and targeted delivery to immune cells [61].

Leukocyte-based biomimetic nanoparticles, such as leukosomes, have shown potential for combined targeted and immunotherapy approaches in osteosarcoma [125]. Leukosomes can effectively deliver multi-tyrosine kinase inhibitors (mTKIs) to induce an immunogenic response in osteosarcoma. These nanoparticles can deliver immunomodulatory agents while evading immune clearance, potentially enhancing the overall immune response against tumor cells.

Cholesterol-bearing polysaccharide-based nanogels have demonstrated utility as drug delivery systems and scaffolds for immunotherapy and regenerative medicine [126]. These nanogels can encapsulate and release immunomodulatory agents, providing a versatile platform for enhancing antitumor immune responses. Lipid-based nanoparticle combination immunotherapy systems have also shown promise, combining agonists of the Stimulator of Interferon Genes (STING) and Toll-like Receptor 4 (TLR4) pathways to promote antitumor immunity [127, 128]. Hydrogel-based systems, such as methacrylated glycol chitosan (MGC) hydrogels, have demonstrated the ability to activate tumor-related immune cells both locally and over a prolonged period, enhancing immunotherapeutic efficacy [129]. These hydrogels can serve as depots for the sustained release of immunomodulatory agents, potentially overcoming the limitations of systemic administration.

Biomaterial-based vaccine delivery systems have also been explored for osteosarcoma treatment. These systems can enhance the stability and immunogenicity of tumor-associated antigens, potentially eliciting more robust and durable antitumor immune responses. Nanoparticle-based vaccine formulations, including those based on PLGA or liposomes, have shown promise in delivering tumor antigens and adjuvants to antigen-presenting cells, promoting effective T cell responses against osteosarcoma [130]. Moreover, checkpoint inhibitor delivery platforms, such as hydrogels and microspheres designed to locally release anti-PD-1 or anti-PD-L1 antibodies, have shown promise in enhancing intratumoral immune activation while reducing systemic toxicity. For example, thermosensitive hydrogels loaded with anti-PD-L1 have demonstrated improved tumor infiltration of cytotoxic T cells in murine osteosarcoma models. In addition, biomaterial-assisted CAR-T cell delivery is an emerging strategy aimed at improving cell retention and activation within the tumor microenvironment. While CAR-T therapy for solid tumors like osteosarcoma remains challenging due to poor infiltration and immunosuppression, biodegradable scaffolds and nanoparticles have been investigated as supportive platforms to modulate local cytokine levels and improve T-cell viability.

Immunotherapy for osteosarcoma leverages biomaterial-based delivery systems, such as nanoparticles, nanogels, hydrogels and vaccines, to enhance immune responses by ensuring targeted delivery, sustained release and protection of immunotherapeutic agents (Figure 5). These innovations aim to improve antitumor immunity and overcome the limitations of conventional systemic therapies.

Figure 5.

Schematic illustration of biomaterial-based immunotherapy strategies for osteosarcoma. This figure summarizes key delivery platforms and mechanisms by which biomaterials enhance antitumor immune responses in osteosarcoma. (A) Leukocyte-mimetic NPs exploit immune evasion and targeting properties to accumulate in the tumor microenvironment, where they gradually release immunomodulatory agents (e.g. checkpoint inhibitors or cytokines) to reshape the local immune milieu. (B) Injectable hydrogels act as localized depots for sustained release of cytokines and tumor-associated antigens. These hydrogels recruit dendritic cells, which present antigens and activate CD4⁺ T cells and CTLs, enhancing localized immune activation and minimizing systemic exposure. (C) Antigen-loaded nanoparticles are internalized by APCs, escape lysosomal degradation and process antigens through both MHC-I and MHC-II pathways. This dual presentation activates CD8⁺ cytotoxic T cells and CD4⁺ helper T cell subtypes (e.g. Th1, Th17), resulting in a coordinated antitumor response. These biomaterial-enabled immunotherapies offer a promising strategy to enhance tumor-specific immunity, extend therapeutic duration and reduce off-target effects in osteosarcoma treatment. Created with BioRender.com.

In conclusion, biomaterial-based delivery systems offer diverse and promising approaches for enhancing the efficacy of drug delivery, gene therapy and immunotherapy in osteosarcoma treatment. These systems leverage the unique properties of various biomaterials to overcome challenges associated with traditional therapies, such as poor bioavailability, off-target effects and limited efficacy. As research in this field continues to advance, the integration of these innovative approaches into clinical practice holds great promise for improving outcomes for osteosarcoma patients. Future directions may include the development of multifunctional delivery systems that combine different therapeutic modalities, as well as personalized approaches tailored to individual patient characteristics and tumor profiles. Continued research and interdisciplinary collaboration will be crucial for translating these promising biomaterial-based strategies into effective clinical treatments for osteosarcoma.

Smart/stimuli-responsive biomaterials

Innovative biomaterials employed in osteosarcoma therapy often incorporate controlled drug release mechanisms to improve treatment precision and minimize systemic toxicity [131]. These systems typically operate through a combination of passive and responsive modalities. In many polymeric carriers and porous scaffolds, drug release is primarily governed by diffusion and the gradual degradation of the matrix material, as seen in widely used PLGA and PCL systems, allowing for sustained and programmable drug exposure over time [16].

Building upon these strategies, stimuli-responsive or “smart” biomaterials have rapidly emerged as promising therapeutic platforms for osteosarcoma due to their capacity to dynamically respond to specific internal or external cues in the tumor microenvironment [132]. Unlike conventional passive drug delivery systems, smart biomaterials are designed to recognize and respond to pathophysiological signals such as pH gradients, ROS, specific enzymes, temperature shifts or redox conditions [133]. This allows for spatiotemporally controlled drug release, enhanced therapeutic specificity, reduced systemic toxicity and even integration of diagnostic and therapeutic functionalities. The osteosarcoma microenvironment, characterized by acidity, oxidative stress, enzyme overexpression and hypoxia, offers distinct molecular targets that make smart biomaterials particularly advantageous in overcoming challenges such as drug resistance, poor targeting and severe side effects.

Among these systems, pH-responsive platforms are the most extensively studied. For example, Zhu et al. developed a pH-sensitive hydrogel based on a self-assembling nonapeptide (P1) for targeted delivery of doxorubicin (DOX). The hydrogel remained stable under physiological pH but significantly accelerated DOX release under acidic conditions (3.6-fold higher release at pH 5.8 than at pH 7.4) [134]. In vivo studies demonstrated enhanced DOX accumulation at tumor sites and superior antitumor efficacy, highlighting its therapeutic potential and biocompatibility. Similar pH-responsive systems using chitosan-based nanocarriers have also been applied for siRNA delivery to silence key oncogenes within osteosarcoma cells.

ROS-responsive systems exploit elevated intracellular ROS levels in tumor cells as a trigger for drug release [135]. A representative example is the development of a self-adaptive, multifunctional RPSH hydrogel incorporating dual-responsive R/I@SeNP nanoparticles (composed of RRx-001 and ICG) into a PAAm/SA/HA matrix [136]. This hydrogel effectively modulated the postsurgical inflammatory microenvironment by inducing M2 macrophage polarization and triggered the release of immunomodulatory species such as RSeO(OH) upon ROS stimulation, achieving a tumor inhibition rate of 72.84%. Additionally, long-term application of the hydrogel promoted robust bone regeneration, with a BV/TV ratio reaching 59.03% after eight weeks, underscoring its dual functionality in immunomodulation and osteogenesis.

Thermo-responsive systems have also been investigated, primarily for use in combinatorial photothermal therapy and localized chemotherapy [137]. An injectable thermosensitive hydrogel (mPEG₄₅–PLV₁₉) was developed to co-deliver methotrexate and alendronate [138]. This hydrogel rapidly solidified at body temperature, provided sustained drug release and demonstrated excellent physicochemical properties. In vivo results showed significant inhibition of tumor growth, reduction in bone destruction and suppression of lung metastasis, indicating great potential for osteosarcoma chemotherapy.

Studies have also focused on integrating multiple stimuli-responsive mechanisms within a single system to enable synergistic control and combinatorial therapy. This approach holds promise for enhancing precision and efficacy in complex tumor microenvironments. In addition, smart biomaterials are increasingly applied in osteosarcoma immunotherapy and gene therapy [139]. Hydrogels responsive to inflammatory cues have been designed to locally release immunomodulators, such as STING or TLR4 agonists, to activate tumor-specific immune responses. Redox-sensitive liposomes or polymeric nanoparticles have also been employed to deliver siRNA, effectively silencing oncogenic pathways in osteosarcoma cells and offering more targeted and safer gene therapy strategies [140].

Despite the great potential of smart biomaterials, several challenges hinder their clinical translation. These include complex material design, difficulties in large-scale manufacturing, inter-patient variability in stimulus profiles and concerns regarding the long-term biocompatibility and safety of certain responsive components. Moreover, multifunctional systems often face regulatory ambiguity, complicating their path to approval. Future research should prioritize modular design strategies to improve production reproducibility, simplify response mechanisms and utilize fully degradable, nontoxic materials. Interdisciplinary collaboration between materials science, biomedical engineering and clinical oncology will be critical to establish streamlined pathways from in vivo validation to GMP-grade production.

In summary, the integration of smart biomaterials marks a change in thinking in osteosarcoma management, from passive treatment to precision-responsive, multifunctional therapy. By sensitively responding to microenvironmental cues, these systems offer enhanced therapeutic outcomes, combination strategies and reduced toxicity, holding promise as a central component in the future landscape of osteosarcoma treatment alongside drug, gene and immune-based therapies.

To provide a more systematic perspective on recent advances, we compiled a summary of representative studies from 2021 to 2025 that explore biomaterial-based delivery strategies in osteosarcoma therapy. Table 2 presents an overview of 64 original research articles, facilitating comparative analysis across biomaterial types, therapeutic payloads and functional mechanisms. This classification underscores the translational potential of multifunctional delivery systems and helps identify promising directions for future development. Notably, the included studies cover both single-material delivery systems, such as polymeric nanoparticles, liposomes or hydrogels and integrated platforms that combine multiple biomaterial types with synergistic therapeutic modalities. These multifunctional constructs often couple drug delivery with gene or immunotherapy, offering more comprehensive approaches to overcome tumor resistance and enhance localized treatment efficacy.

Table 2.

Advanced research of biomaterial-based delivery systems in osteosarcoma treatment with therapeutic classification.^a

Biomaterial carrier	Therapeutic agents	Targeting strategy	Release mechanism	Treatment efficacy	Ref.
Sr²+/UV double-crosslinked alginate–GelAGE with PDA particles	DOX	Combined chemotherapy + photothermal therapy	DOX controlled release; PDA-mediated hyperthermia; Sr²+ ion release	Kills MG63 osteosarcoma cells via chemo-PTT synergy; promotes rBMSCs proliferation and ALP activity; osteogenic and antitumor dual-function validated in vitro	[141]
Gallium-doped bioactive glass	Gallium oxide	Selectively toxic to osteosarcoma cells, sparing normal osteoblasts	Sustained release via dissolution	99% reduction in Saos-2 viability; stimulated apatite layer formation in SBF	[142]
Chitosan-grafted PCL nanofibers loaded with bioactive glasses (BGs)/MBGs	Cisplatin	Local hyperthermia via alternating magnetic field enhances chemotherapy effect on osteosarcoma MG-63 cells	pH 5.5 and 43°C temperature accelerate Cisplatin release	Effective apoptosis/necrosis induction in MG-63 cells in vitro; potential for implantable bone tumor therapy device in vivo	[143]
Chitosan microspheres	Curcumin and Gallic acid	Positive surface charge facilitates cellular interaction and drug loading	Sustained drug release over ∼7 days in physiological buffer	Negligible toxicity to blood and normal cells; strong anti-osteosarcoma effect on U2OS cells	[144]
Chitosan physically crosslinked with Cu(II) ions	DOX	Synergistic inhibition of tumor growth at lower drug dose; selective toxicity toward osteosarcoma cells	Initial burst release followed by sustained release; pH sensitivity facilitates drug loading and release	Selective toxicity to osteosarcoma MG-63 cells; mild toxicity to healthy human mesenchymal stem cells	[145]
Carboxymethyl chitosan nanoparticles labeled with Na131I	DOX and Curcumin	Anti-EGFR targeting; enhanced tumor penetration; photothermal sensitization via curcumin	Higuchi model-governed sustained release; fractionated dose improves efficacy	513-fold greater targeting efficacy to MG-63 cells; 18.3-fold increased cytotoxicity with fractionated dose; induced G2/M cell cycle arrest	[146]
PLGA and chitosan composite with epoxy-tetrapeptide derivative	Paclitaxel (PTX)	pH-responsive drug release targeting acidic tumor microenvironment	Acidic pH-triggered controlled release	Significant inhibition of osteosarcoma HOS and U2OS cell proliferation; dose-dependent SPICE1 suppression; enhanced drug loading and safety profile	[147]
Tropocollagen grafted with partially deacetylated chitin nanocrystals (CO-g-ChNCs)	Octenidine dihydrochloride	Enhanced cytocompatibility and cell adhesion; designed for skin and bone tissue targeting	Controlled drug release via hierarchical microstructure of layered hydrogel membranes	Improved mechanical properties, cytocompatibility and cell adhesion; potential for controlled drug release and tissue regeneration	[148]
Diopside (CaMgSi2O6)	Doxorubicin	Bioactive and degradable ceramic scaffold enabling local drug release	Gradual doxorubicin release from scaffold	In vitro selective cytotoxicity higher in osteosarcoma MG-63 spheroids vs. primary human fibroblasts	[149]
Aliphatic polyesters with closo-borates in polymer/alginate/gelatin hydrogel composite	Closo-borates for BNCT	Localized boron delivery to tumor cells combined with bone defect repair	Controlled degradation and release of closo-borate ions	High potential for boron neutron capture therapy and bone tissue regeneration	[150]
Chemically crosslinked silk fibroin hydrogel with HRP/H2O2	Curcumin	Localized delivery via in situ injection	Rapid gelling via HRP/H2O2-initiated di-tyrosine crosslinking; curcumin-entrapped	Toxic to U2OS osteosarcoma cells; induces rapid apoptosis within 4 hr; β-sheet structure enhanced with curcumin loading	[151]
Chitosan, alginate, hydroxyapatite composite hydrogel	Zoledronic acid	Local bone regeneration scaffold; biocompatible with osteosarcoma cells	Sustained drug release over extended period (48–360 hr)	Biocompatible; increased MG-63 cell viability; porous structure suitable for 3D printing and bone regeneration	[152]
Apatite-infused sol-gel glass	DOX	Osteoinductive + drug reservoir	Mesoporous nanostructure	ALP↑; mineralization↑	[153]
Biodegradable polyelectrolyte complex (PEC) from chitosan + nascent HAp	Ciprofloxacin	Osteoconductive hydroxyapatite combined with biodegradable PEC for targeted bone delivery	Controlled drug release via swelling and degradation kinetics of composite	Cytocompatible with MG-63 and HOS cells; early biomimetic apatite mineralization; antibacterial activity against S. aureus and E. coli in vitro	[154]
Hierarchically structured HAp microspheres integrated with amphiphilic curcumin prodrug	Curcumin	Selective uptake by osteosarcoma cells; enhanced loading and stability via hierarchical flake-like HA structure	Prodrug self-assembly influenced by hierarchical structure; controlled cargo delivery	Suppressed tumor growth and metastasis; promoted apoptosis; inhibited proliferation and tumor vascularization	[155]
MgO-doped tricalcium phosphate (TCP) scaffolds	Curcumin	Uptake by osteosarcoma cells, intracellular ROS increase via SO2 release	Sustained release of Curcumin (∼22% in 30 days at pH 7.4)	Enhanced bone formation (∼2.5x control), 8.5x osteosarcoma cell viability reduction and 71% antibacterial efficacy in vivo rat model	[156]
TCP coated with HAp	Curcumin and Vitamin D3	Bone graft matrix supporting osteogenesis and anticancer activity	Sustained release from CaP matrix and HA coating	2.7-fold increase in new bone formation in vivo after 6 weeks; decreased osteosarcoma cell viability in vitro after day 11	[157]
Amorphous calcium phosphate and bone-like carbonated nanocrystalline apatite	DOX	Localized delivery; implantable paste for bone defect filling	Controlled local release of doxorubicin from loaded particles	Limited lung metastasis and no signs of toxicity in invasive osteosarcoma rat model	[158]
Octacalcium phosphate	DOX	Osteoconductive + pH-sensitive	Sustained release (6 weeks)	Apoptosis via PARP; MC3T3-E1 proliferation↑	[159]
CaS/HA composite	DOX	Intratumoral depot	Time/pH-sensitive release	Tumor inhibition; enhanced local concentration	[160]
Gelatin/PLA + DOX@nHAp + Icariin	DOX + Icariin	Dual: tumor + bone repair	Burst + sustained release	MG-63 apoptosis; ALP↑; biomineralization↑	[161]
Eggshell-derived hydroxyapatite	Etoposide	Dual: antitumor + antibacterial	Wet-precipitated sustained release	MG-63 apoptosis↑; anti-S. aureus activity↑; L929 cytocompatibility	[162]
HAp porous beads (HAPB)	Gentamicin and Vancomycin	Localized delivery via muscle implantation; bioceramic scaffolds for antibiotic release	Sustained antibiotic release with demonstrated biocompatibility	No sub-chronic systemic toxicity observed in rabbits; noncytotoxic to osteosarcoma cells; supports regulatory approval potential	[163]
Poly(L-lactic acid) (PLLA)/nanoscale HAp	Metformin	Combines mechanical strength, bioactivity and water-soluble antitumor MET	Biodegradation of PLLA enables slow sustained MET release	Promoted osteosarcoma cell apoptosis and tumor inhibition in vitro; enhanced osteogenic differentiation of BMSCs	[164]
HAp/BSA	Paclitaxel	Tumor targeting via HA; anti-metastasis	Sustained release of PTX and Ca²+	Inhibited 143B cell proliferation/migration; promoted osteogenic differentiation in hFOB 1.19	[165]
TCP and PCL composite	Quercetin and potassium chloride (KCl)	Bone tissue engineering scaffold with tunable degradation and drug release	Biphasic diffusion-mediated quercetin release over 28 days	2.1-fold increase in human fetal osteoblast viability; 3-fold reduction in osteosarcoma MG-63 cell viability; antibacterial activity against S. aureus	[166]
Mg, Si-doped HAp + sodium alginate + chondroitin sulfate/keratin	Raloxifene hydrochloride	Local delivery to bone via implantable beads	Sustained release over 12 weeks; no burst release; Mg²+ crosslinking enhances surface properties	Beads show porous structure, high mechanical stability and prolonged drug release; cytocompatible with osteoblasts, active on OS cells	[167]
β-TCP scaffold	Zoledronic acid (ZOL)	Localized bone-targeted delivery via bound and free ZOL states	Limited release of ZOL; majority bound to scaffold allowing sustained effect	Inhibited osteosarcoma and osteoclast activities; promising novel bone substitute	[168]
Lipid	Alendronate, Cisplatin	Bone homing via bisphosphonate	Controlled lipid release	Low systemic toxicity; effective tumor control	[169]
Polyhydroxybutyrate-co-hydroxyvalerate (PHBV) with mesoporous bioactive glass nanoparticles	Cinnamaldehyde (CIN)	Antibacterial and bioactive; selective activity against Staphylococcus aureus and Escherichia coli; supports MG-63 proliferation	Sustained cinnamaldehyde release up to 7 days	Antibacterial activity demonstrated; no adverse effect on osteosarcoma MG-63 cell viability; rapid hydroxyapatite formation showing bioactivity	[170]
Mesoporous silica nanoparticles (MSNs) coated with HA	DOX and Selenium (Se)	HA gatekeeper enables pH-responsive intracellular release; dual drug delivery enhances osteosarcoma inhibition	pH-triggered degradation of HA coating allowing controlled release of Dox and Se	Enhanced osteosarcoma inhibitory efficiency in vitro for combination therapy vs. single-agent treatments	[171]
Selenium-doped nano-HAp and mesoporous HAp	DOX and Se	Higher selenium doping and Dox loading in n-HA; selective uptake by osteosarcoma cells	Similar Dox release kinetics; selenium release higher in n-HA; sustained release behavior	Potential dual function inhibiting osteosarcoma recurrence and promoting osteogenesis	[172]
Mesoporous silica (Se-doped or Se-coated)	Selenium (SeO3²− or SeNP)	ROS induction + osteoblast safety	GSH/NADPH-sensitive release	Selective cytotoxicity (Saos-2↑; osteoblast↓); apoptosis via ROS	[173]
Methylcellulose	Curcumin + IR820	Minimally invasive chemo-PTT	Thermal-triggered gelation	Tumor ablation; ALP↑; MSC osteogenesis↑	[174]
Biodegradable nanocement with Cissus quadrangularis herbal membrane	DOX	Local delivery to tumor resection site; combined tumor cell killing and periosteum/bone formation enhancement	Sustained doxorubicin release over 30 days; herbal membrane supports periosteum and mineralization	2.6-fold increase in bone volume; effective tumor cell killing; periosteum development and mineralized bone callous formation in vivo	[175]
CS-SA/CS-FA + Fe3O4 magnetic nanoparticules	DOX	pH-sensitive + folate receptor targeting	pH-triggered release + magnetic targeting	MG-63 specific uptake and apoptosis; A549 safety profile	[176]
Iron oxide nanoparticles coated with boiling rice starch extract	DOX	Photothermal therapy guided by photoacoustic imaging (PAI); bioactive rice starch coating enhances targeting	pH-dependent drug release in acidic, neutral and basic media; physical immobilization coating of Dox	Excellent photothermal stability and conversion; biocompatible; promising theranostic applications	[177]
Natural melanin nanoparticles from Sepia officinalis ink	DOX	Chemo-photothermal therapy triggered by NIR light; biocompatible, cost-effective natural nanoplatform	Sustained drug release enhanced by photothermal stimuli	93% reduction in SaOs-2 osteosarcoma cells viability after 48 hr with NIR; synergistic chemo-photothermal antitumor effect	[178]
LDH/PCL	Alendronate	Controlled release via LDH intercalation in PCL	Sustained release enhanced with 15 wt% LDH	Increased MG-63 viability, attachment and mineralization; stable ALP activity	[179]
Zr-HA + modified PCL  +  β-CD	Cisplatin + Curcumin	Dual spatial/temporal targeting	Porosity + inclusion complex	Tumor suppression; osteoinduction↑	[180]
PCL composite films modified with BG particles	Polyphenols extracted from Salvia officinalis L.	BG particles modulate polyphenol release kinetics and polyphenol-binding capacity for selective osteosarcoma cytotoxicity	Controlled polyphenol release influenced by BG texture and surface chemistry	Selective cytotoxicity and antiproliferative effect on osteosarcoma Saos-2 cells; no toxicity to normal osteoblasts	[181]
HEMA/MMA + phosphate coating	DOX	pH-responsive + osteogenic	Degradation + acid-triggered release	MG-63 apoptosis; post-treatment CaP formation	[182]
PLGA + PEG4000 implant	DOX	Local depot delivery	Three-phase release profile	Local drug accumulation↑; systemic toxicity↓	[183]
PLGA core + 143B-RAW hybrid membrane	Paclitaxel	Tumor homing + immune evasion	Sustained release + chemotaxis	Xenograft inhibition; low off-target toxicity	[184]
mPEG-b-P(C7-co-CA) amphiphilic polymeric prodrug micelles	Cinnamaldehyde	pH-triggered charge conversion (neutral to positive) targets acidic osteosarcoma environment (pH 6.5)	pH-dependent drug release via polymer micelle destabilization	High in vitro anti-osteosarcoma efficacy; increased ROS generation and apoptosis in 143B cells	[185]
Polymethylmethacrylate (PMMA) cement with CMC additive	Cisplatin	Porosity introduced for localized cisplatin delivery while maintaining mechanical strength	Sustained release of cisplatin (∼18% over 28 days)	Efficient osteosarcoma cell killing in vitro; compressive strength comparable to intact tibias; viable for load-bearing bone defect treatment	[186]
Polydopamine (PDA)-modified silk fibroin (SF) composite scaffold	Curcumin	Localized delivery combining photothermal effect and chemotherapy for synergistic osteosarcoma targeting	Low pH and NIR irradiation accelerate CM release	Long-term stable anticancer effect; enhanced osteosarcoma MG-63 inhibition under NIR; promotes osteoblast proliferation	[187]
Bacterial exopolysaccharide	Curcumin	pH-responsive release targeting acidic tumor microenvironment	pH-dependent release, higher release at acidic pH	Cytotoxicity against osteosarcoma MG-63 cells; superior stability, hemocompatibility, antibacterial, antibiofilm and antioxidant activity	[188]
PEG	DOX	PEG reduces protein adsorption and cardiotoxicity; UV-triggered PEG detachment enhances uptake	UV-induced cleavage of amide bond detaches PEG, increasing Dox cellular uptake	No significant organ toxicity; efficient tumor suppression observed in osteosarcoma models	[189]
Chondroitin sulfate (marine-derived polysaccharide)	N/A (nanoparticles themselves therapeutic)	Biocompatible marine polysaccharide coating enhances nanoparticle stability and delivery	Passive uptake, no drug release per se	Selective cytotoxicity against osteosarcoma MG63 cells by ROS-mediated mitochondrial damage; apoptosis activation confirmed by flow cytometry	[190]
Amphiphilic polymer (mPEG-P(HDI-DN))	Sulfur dioxide (SO2) gas therapy agent	–	GSH-triggered degradation of polymer releasing SO2 gas	Effective osteosarcoma growth inhibition without obvious tissue toxicity in vivo	[191]
Bioglass + PVA + Cellulose (CNC) + SA	Methotrexate (MTX)	Localized delivery	Diffusion + Bioglass-tuned	MG-63 cytotoxicity; sustained release	[192]
Silk fibroin + nHA + Curcumin-modified PDA	Curcumin	Chemo-PTT + bone regeneration	Photothermal + sustained	Tumor suppression + in vivo bone regeneration	[193]
Alendronate-conjugated polyethylene glycol functionalized chitosan (ALD-PEG-CHI)	Cell death siRNA (CD-siRNA) and Curcumin (CUR)	Bone targeting via alendronate conjugation; synergistic cytotoxicity of siRNA and CUR delivery	Encapsulation and controlled release; size < 200 nm; near-neutral zeta potential	In vitro synergistic growth inhibition of MCF-7 cells; 5-fold enhanced bone targeting compared to controls	[194]
PLGA + Chitosan core + pectin/chitosan shell	miRNA-34a + Dox + Resveratrol	Gene + chemo therapy	Layer-by-layer release	U2OS/Saos-2 apoptosis ↑; synergistic effect	[195]
Chitosan modified with cell-penetrating peptide (H6R6), thermosensitive hydrogel	Doxorubicin and siRad18 siRNA	Enhanced tumor permeability via peptide-modified NPs; siRNA-mediated gene silencing to overcome Dox resistance; combined with PD-L1 immune checkpoint blockade	Controlled nanoparticle release from thermosensitive hydrogel	Significant inhibition of osteosarcoma growth and lung metastasis in vivo; enhanced immunogenic cell death; improved chemo- and immunotherapy efficacy	[53]
Hyaluronic acid hydrogel + nanoparticles	microRNA-29b	Localized delivery to osteosarcoma orthotopic tumor site; combined with systemic chemotherapy	Sustained local release via hydrogel matrix	Reduced tumor burden, increased survival, decreased osteolysis and normalized bone homeostasis in vivo	[196]
Alginate-based hydrogel with hyaluronic acid and gelatin	Reactive Oxygen and Nitrogen Species generated from Cold Atmospheric Plasma	Dual action: selective cytotoxic anticancer agent against osteosarcoma and promoter of stem cell-mediated bone regeneration	Controlled and localized delivery of plasma-derived RONS within hydrogel	Selective cytotoxicity against osteosarcoma MG-63 cells; promotion of human mesenchymal stem cells proliferation and osteogenic differentiation	[197]
Hybrid tumor and macrophage membranes coated on PLGA nanoparticles	microRNA-665	Tumor and macrophage membrane camouflage for tumor targeting; modulation of tumor microenvironment macrophages	Nanoparticle encapsulation; targeted delivery via membrane cloaking	Promoted M1 macrophage polarization, inhibited osteosarcoma MG-63 proliferation and migration; significant tumor growth inhibition in vivo; good biosafety	[198]
CO2-derived cationic poly(vinylcyclohexene carbonates)	siRNA targeting PLK1	Gene silencing of PLK1; biodegradable nonviral vector	Endosomal escape and gene transfection	Induced G2/M arrest and apoptosis; significant tumor regression in vitro and in vivo	[116]
Mg2+-releasing hydrogel	Anti-PD-L1 + Vismodegib + Mg2+	Immunotherapy + bone regeneration	Sustained release	Tumor suppression; osteogenic gene upregulation	[199]
Thermosensitive and zwitterionic polymer + mesoporous nanoparticles	Immune Checkpoint Blockade (ICB) agents	Local delivery to surgical site; thermogel prevents early leakage and increases tumor-site drug accumulation	NIR-induced heat triggers retro Diels–Alder reaction to degrade nanoparticle coating, enabling controlled ICB release	Effective prevention of osteosarcoma recurrence; enhanced T cell activation; favorable biocompatibility observed	[200]

^aThis table compiles 64 representative original research articles on biomaterial-based delivery systems applied in osteosarcoma treatment from 2021 to 2025. This classification facilitates comparative analysis of biomaterial platforms and their associated therapeutic strategies in osteosarcoma research and development.

Biomaterials for bone regeneration in osteosarcoma treatment

While the previous discussion focused on biomaterials for tumor-targeted therapies, another essential goal in osteosarcoma management is the restoration of bone integrity after surgical resection. The treatment of osteosarcoma presents a unique challenge in the field of bone tissue engineering, as it requires not only the elimination of residual tumor cells but also the promotion of bone regeneration in the affected area (Figure 6). Recent advancements in biomaterials and cell-based therapies have shown promising results in addressing these dual needs, offering new hope for improved patient outcomes.

Figure 6.

Schematic illustration of integrated bone tissue engineering strategies for osteosarcoma. This figure outlines multifunctional biomaterial approaches designed to address both tumor eradication and post-resection bone defect repair following osteosarcoma surgery. (A) After surgical excision of the tumor, scaffolds and therapeutics aim to eliminate residual osteosarcoma cells while promoting angiogenesis and osteogenesis to restore bone integrity. (B) BGNF-based 3D matrices fabricated via crosslinking of bioactive glass nanofibers and gelatin provide structural support and stimulate biomineralization, with intrinsic antimicrobial properties. (C) Mesoporous bioactive glass nanoparticles, doped with ions such as Ga³⁺, Ca²⁺ and ${\text{PO}}_4^{3-}$, enable targeted drug release and anticancer effects through TfR1-mediated endocytosis, inducing tumor cell death. (D) 3D-printed composite scaffolds incorporating materials such as MXene, silk fibroin, collagen and quercetin enable photothermal activation under near-infrared light to selectively ablate tumor cells while supporting osteogenic regeneration. (E) Gene-activated scaffolds and stem cell-based constructs, using MSCs or ADSCs combined with plasmid DNA, RNA activation systems or signaling molecules, promote bone-forming cell differentiation and angiogenesis through localized gene expression. These strategies combine biochemical, biophysical and cellular interventions to create a regenerative microenvironment that supports bone healing while suppressing tumor recurrence. Created with BioRender.com.

Bioactive 3D scaffolds: promoting bone cell proliferation postsurgery

Three-dimensional scaffolds play a crucial role in bone tissue engineering by providing a structural framework that mimics the natural extracellular matrix, supporting cell adhesion, proliferation and differentiation [201]. In the context of osteosarcoma treatment, these scaffolds serve as temporary substitutes for the removed bone tissue, guiding the regeneration process [202]. The development of multifunctional nanofibrous 3D matrices has shown particular promise, combining the benefits of tissue engineering with photothermal therapy for postoperative treatment of osteosarcoma [203].

One innovative approach involves the use of flexible bioactive glass nanofibers (BGNFs) as the basic building blocks of these scaffolds [204]. When combined with genipin-crosslinked gelatin (GNP-Gel), these materials form stable 3D structures that closely resemble the extracellular matrix. The porous nature of these scaffolds, achieved through ice crystal templating and freeze-drying techniques, allows for efficient cell infiltration and nutrient transport. Moreover, the excellent compression recovery performance of these matrices in water makes them suitable for minimally invasive surgical applications, a significant advantage in postoperative care.

The incorporation of bioactive materials such as HAp and bioactive glass into scaffold designs has revolutionized bone tissue engineering [205]. These materials not only provide structural support but also actively stimulate bone cell proliferation and differentiation, accelerating the healing process. Hydroxyapatite-tricalcium phosphate (HAP-TCP) bioceramics have demonstrated remarkable osteoinductive and osteointegrative properties in experimental studies. When used to fill metaphyseal defects, these materials promote a dynamic and uncomplicated course of reparative osteogenesis [206]. The gradual arrangement of osteoclasts and osteoblasts on the surface of HAP-TCP implants indicates high biocompatibility with bone tissue, facilitating the processes of implant resorption, mineralization and the formation of mature bone tissue [207]. Bioactive glasses, particularly those containing boron (e.g. 13-93B20), have shown enhanced reactivity compared to traditional silicate glasses [208, 209]. Hybrid scaffolds combining these bioactive glass particles with gelatin exhibit faster initial dissolution and more rapid precipitation of a HAp layer, which is crucial for bone bonding and regeneration. The ability to tailor glass composition allows for better control over material dissolution, biodegradability and bioactivity, making these hybrids promising candidates for bone applications in osteosarcoma treatment.

The development of multifunctional biomaterials that can simultaneously address cancer treatment and bone regeneration represents a significant advancement in osteosarcoma therapy. Gallium-doped bioactive glasses have shown promising results in this regard, demonstrating the ability to selectively kill human osteosarcoma cells while promoting excellent in vivo osteointegration [210]. Studies have shown that cell culture media conditioned with gallium-doped bioactive material can kill up to 41% of osteosarcoma cells without significantly affecting normal human osteoblasts. Furthermore, in vivo experiments have demonstrated excellent material-bone integration with no signs of local toxicity or implant rejection. This approach offers the potential for synergistic bone regeneration and targeted cancer therapy, paving the way for new bone cancer treatment strategies that address both tumor elimination and tissue regeneration in a single material.

Recent developments in scaffold design have focused on creating structures that more closely mimic the complex architecture of natural bone [211]. This biomimetic approach enhances bone healing post-tumor removal by providing an environment that closely resembles the native tissue. Notable advancements include the development of MXene-integrated (Ti₃C₂) silk fibroin-based self-assembly-driven 3D-printed scaffolds, which offer combined photothermal tumor ablation and osteogenic support, as well as silk fibroin/polyacrylamide-based tough 3D-printed scaffolds with strain-sensing capacity and chondrogenic activity, demonstrating the versatility of silk fibroin in multifunctional scaffold engineering [212, 213]. These theragenerative scaffolds combine the benefits of a controlled pore size and macroscopic geometry with mechanical stability. The integration of MXene two-dimensional nanosheets into the scaffold structure endows it with a remotely controlled photothermal anti-osteosarcoma ablation function. This dual functionality allows for both the elimination of residual cancer cells through photothermal therapy and the stimulation of bone mineral deposition on the scaffold surface.

Cell-based and gene-based therapies: enhancing bone repair

The incorporation of stem cells and osteoblasts into biomaterial scaffolds has emerged as a powerful strategy to enhance bone repair in osteosarcoma cases [214]. Mesenchymal stem cells (MSCs), in particular, have shown great promise due to their ability to differentiate into bone-forming cells and their secretion of bioactive factors that promote tissue regeneration [215]. Recent advancements in biomaterials have focused on creating scaffolds that not only support but also actively promote stem cell differentiation [216]. These scaffolds are designed to provide the necessary physical and biochemical cues to guide MSCs towards an osteogenic lineage. For example, the combination of MSCs with biocompatible scaffolds has been shown to improve cell tracking and retention at the site of injury, addressing one of the major challenges in cell-based therapies [217]. Adipose-derived stem cells (ADSCs) have gained increasing attention as an alternative to bone marrow-derived MSCs due to their abundant sources, easy availability and multidifferentiation potential [218]. The selection of appropriate biomaterials to be combined with ADSCs is crucial for optimizing their therapeutic effect. Factors such as biocompatibility, inflammation regulation, angiogenesis promotion and osteogenesis induction are key considerations in designing ADSC-loaded scaffolds for bone regeneration in osteosarcoma treatment [219]. In addition to cell-loaded scaffolds, immunomodulatory scaffolds have gained increasing attention for their ability to simultaneously support bone regeneration and suppress tumor recurrence. For example, GelMA-based hydrogels loaded with STING agonists or anti-PD-L1 antibodies can activate local immune responses while promoting osteoblast activity and scaffold integration. Mineralized scaffolds incorporating immunogenic peptides or cytokine-mimicking nanoparticles have also been explored to recruit antigen-presenting cells and remodel the local immune microenvironment in favor of osteogenesis. These dual-function scaffolds represent a promising direction for osteosarcoma treatment, integrating immunotherapeutic potential with regenerative performance.

In bone tissue engineering, to avoid the side effects of inflammation, potential tumorigenicity and ectopic osteogenesis caused by high-dose growth factor administration, researchers have begun to turn to gene therapy and RNA interference (RNAi) technology [220]. Although traditional protein drugs (such as BMP, VEGF, FGF, etc.) can promote osteogenesis and angiogenesis, they are easily degraded and diluted in the body, and require repeated or high-dose administration, which brings a series of safety risks [221]. In contrast, gene and RNAi vectors are transfected/transduced in local cells, so that the cells themselves stably express (or inhibit) the target protein, which can not only maintain long-term efficacy but also reduce side effects caused by high-dose proteins. The two most widely used gene delivery methods are viral vectors (high transduction efficiency but with immune and insertion mutation risks) and nonviral vectors (high safety but low transgenic efficiency) [222]. Combining these vectors with scaffold materials, including gene-activated scaffolds and RNAi-activated scaffolds, they can in situ transduce/transfect host cells after transplantation into the body, thereby inducing the expression of target genes or inhibiting the expression of specific genes [223]. Compared with the method of culturing and genetically modifying cells before transplantation and then implanting them into scaffolds, gene-activated scaffolds are expected to become “ready-made” bone repair alternatives that do not require cell culture operations, reducing problems such as differences in cell sources, cell transportation and operational difficulties. The feasibility and safety of gene therapy have been demonstrated in bone tissue engineering, which can provide ideas for the treatment of malignant bone tumors such as osteosarcoma. On the one hand, gene vectors are used to continuously express proteins that inhibit tumor proliferation or metastasis in the local microenvironment of the tumor; on the other hand, RNAi technology can downregulate the expression of genes related to osteosarcoma growth [224]. The combination of the two may achieve a more lasting and low-toxicity therapeutic effect at both the bone repair and antitumor levels.

In conclusion, the field of bone tissue engineering for osteosarcoma treatment has made significant strides in recent years, with the development of advanced biomaterials and cell-based therapies offering new possibilities for improved patient outcomes. The integration of 3D scaffolds, bioactive materials and stem cell technologies provides a multifaceted approach to addressing the complex challenges of bone regeneration in the context of cancer treatment. As research continues to advance, these innovative strategies hold great promise for enhancing the efficacy of osteosarcoma treatment and improving the quality of life for patients facing this challenging condition.

Challenge and perspective

Among the diverse biomaterial strategies reviewed, some platforms appear particularly promising for clinical translation in osteosarcoma treatment. Multifunctional composite scaffolds that integrate tumor ablation, immune modulation and bone regeneration stand out for their ability to address multiple therapeutic goals simultaneously. For example, Ti₃C₂-MXene-integrated silk fibroin scaffolds have demonstrated both photothermal antitumor activity and osteoinductive potential, highlighting their value in post-resection therapy.

Hydrogel-based systems, due to their injectability, tunable degradation profiles and compatibility with various therapeutic payloads, also show strong adaptability across drug, gene and immunotherapy delivery contexts. In contrast, immune-responsive and gene-activated scaffolds, while conceptually advanced, remain mostly in early-stage development and face greater translational hurdles, including delivery precision and preclinical validation in bone tumor models.

Biomaterial-based strategies for osteosarcoma therapy face significant challenges that span from immunological responses to the complexities of the tumor microenvironment. On one hand, implanted biomaterials often trigger immune reactions, such as inflammation, encapsulation or rejection, that compromise therapeutic efficacy and potentially worsen the tumor microenvironment [225, 226]. Surface modification techniques and the integration of specific metal dopants can help modulate the immune response by creating more biocompatible interfaces [227, 228]. On the other hand, the harsh osteosarcoma microenvironment, characterized by hypoxia, acidosis and high interstitial fluid pressure, poses additional barriers to drug delivery and tissue regeneration [229]. Overcoming these obstacles requires biomaterials capable of adaptive or smart responses, such as engineered extracellular vesicles or nanoparticles designed to release therapeutic agents in direct response to local environmental cues [230–232].

In addition to biological and design-related challenges, the translation of biomaterials into clinical practice presents significant hurdles. Regulatory approval requires comprehensive assessment of sterility, safety and long-term performance, all of which vary by material class and region. Many complex or multifunctional biomaterials also face obstacles in large-scale, GMP-compliant production, owing to batch variability or bioactivity loss during processing. Sterilization techniques such as gamma irradiation or ethylene oxide can damage sensitive therapeutic components, and maintaining functional stability during storage and transportation remains difficult. To address these challenges, researchers are exploring bioactivity-preserving sterilization methods (e.g. supercritical CO₂ or aseptic lyophilization), cryopreservation-compatible scaffolds and modular manufacturing approaches aligned with regulatory frameworks. Early collaboration with regulatory agencies and the adoption of standardized protocols for material characterization and quality control will be key to accelerating clinical translation of biomaterial-based therapies for osteosarcoma.

Looking ahead, multiple innovative directions hold promise for enhancing osteosarcoma treatments. Smart nanomaterials, like dendrimers, nanogels and stimulus-responsive polymers, can target osteosarcoma more precisely and deliver therapeutics with spatiotemporal control [18, 233]. Personalized biomaterial scaffolds, tailored to patients’ genomic and proteomic profiles, may further optimize therapeutic outcomes by matching individual tumor characteristics and bone structures [234, 235]. Additionally, multifunctional and hybrid systems, such as 2D mesoporous silica@MXene or Ti6Al4V-based composites, illustrate how diagnosis and therapy can be combined within a single platform to ablate cancer cells while encouraging bone regeneration [236, 237]. The integration of inorganic components, like black phosphorous, magnesium, zinc, copper, silver, into responsive biomaterials also shows potential for improved biodegradation, antibacterial activity and tumor suppression [238, 239]. While these emerging strategies collectively represent exciting progress, some appear particularly well-positioned for near-term clinical translation. Multifunctional composite scaffolds, capable of simultaneously supporting tumor suppression, immune modulation and bone regeneration, are among the most promising, due to their integrative design and alignment with surgical practice. Similarly, microenvironment-adaptive systems, such as pH- or hypoxia-responsive hydrogels, offer improved therapeutic specificity while minimizing off-target effects. In contrast, although personalized scaffolds based on omics data or patient-derived structures represent a compelling vision for the future, their widespread application is currently constrained by challenges in cost, standardization and regulatory acceptance. Likewise, diagnostics, therapeutic hybrid platforms, though technologically sophisticated, may require further simplification for scalable and robust deployment. Achieving these goals will require close collaboration among materials scientists, immunologists and clinicians, as well as partnerships between academia, industry and healthcare providers to navigate technical, regulatory and scalability challenges. Through continued interdisciplinary innovation, biomaterials stand to transform osteosarcoma treatment and offer new hope to patients facing this aggressive disease. Therefore, materials that balance functional complexity with manufacturability, safety and translational feasibility are likely to lead the next phase of innovation in osteosarcoma biomaterials.

Conclusion

This comprehensive review highlights the transformative potential of biomaterials in osteosarcoma treatment across multiple therapeutic domains. This work stands out for its comprehensive coverage of diverse biomaterial applications in osteosarcoma treatment. It uniquely integrates insights from drug delivery, gene therapy and bone regeneration, providing a holistic view of the field. The review’s novel points include the emphasis on multifunctional biomaterials that combine therapeutic delivery with diagnostic capabilities, the exploration of nature-inspired delivery systems like leukosomes and calcium-modified diatoms, and the detailed discussion of advanced scaffold designs that mimic bone architecture. Additionally, this review introduces the emerging class of smart or stimuli-responsive biomaterials, which respond to tumor-specific cues and offer new avenues for precision-controlled therapy. A summary of 64 recent studies is provided to compare biomaterial-based delivery strategies, emphasizing the promise of multifunctional and composite systems in osteosarcoma treatment.

Despite these advances, several challenges remain, including material immunogenicity, delivery efficiency in the complex tumor microenvironment and regulatory barriers to clinical translation. Future research should prioritize the development of microenvironment-adaptive materials, personalized scaffolds tailored to tumor and bone profiles and clinically scalable fabrication methods. Collaborative efforts across materials science, oncology and translational medicine will be essential to bridge the gap between laboratory innovation and patient-centered application.

Overall, this review offers not only a comprehensive summary of current strategies but also a roadmap for designing next-generation biomaterials capable of reshaping the therapeutic landscape of osteosarcoma.

Funding

This work was supported by grants from the Dalian Science and Technology Innovation Foundation (2022JJ13SN088 to J.H.) and the Liaoning Provincial Natural Science Foundation of China (2023-MS-343 to Q.M.).

Conflicts of interest

None declared.