Background
Osteosarcoma is the most prevalent primary malignant bone tumor in children and adolescents. The current standard treatment involves a combination of chemotherapy and radical surgical resection. This approach, however, confronts two major clinical challenges: a high risk of postoperative recurrence and metastasis, and the creation of extensive bone defects that severely impair functional recovery and long-term quality of life.

The advancement of biomaterials technology offers a promising strategy to address these dual challenges concurrently. These materials can function as localized drug delivery systems that enhance antitumor efficacy while minimizing systemic toxicity. Moreover, they have facilitated the application of novel therapeutic modalities, such as photothermal, magnetic hyperthermia, microwave thermal, chemodynamic, and sonodynamic therapies. Crucially, these biomaterials are also designed to provide structural support and biological cues for bone regeneration, thereby fulfilling the goal of bifunctional integration.

This review presents a systematic and innovative classification of these cutting-edge bifunctional biomaterials. It provides a critical analysis of their design principles, therapeutic efficacy, and clinical translation potential, with the aim of establishing a new theoretical framework and proposing future research directions for the comprehensive postoperative management of osteosarcoma.

Research Progress
This review innovatively categorizes bifunctional biomaterials for post-osteosarcoma repair into three distinct strategic paradigms (Fig.1):
The traditional bifunctional strategy achieves initial functional integration by co-loading antitumor components and osteogenic components within a single carrier. Some studies further endow these systems with auxiliary capabilities such as temperature monitoring and reactive oxygen species scavenging. However, due to the simultaneous release and action of both active components, this approach still presents inherent limitations in functional synergy: the hostile microenvironment created during antitumor therapy (e.g., hyperthermia, ROS) may inhibit bone regeneration, while prematurely initiated tissue repair could potentially compromise complete tumor eradication.

The enhanced antitumor bifunctional strategy aims to further improve therapeutic efficacy on the basis of dual-function integration. Through sophisticated material design, this approach enhances tumor-killing effectiveness via two main pathways: optimizing unitary therapies (such as inhibiting heat shock proteins to enhance photothermal efficacy, or supplementing substrates for chemodynamic therapy), or constructing multimodal synergistic treatment systems (e.g., chemo-photothermal combination, photothermal-chemodynamic synergy). These advancements enable more thorough tumor clearance, thereby creating favorable conditions for subsequent bone regeneration.

The temporally regulated bifunctional strategy, as a more intelligent research direction, focuses on resolving the temporal conflict between functions. By designing differential release kinetics, constructing core-shell structures, or incorporating external stimulus-responsive mechanisms, this strategy achieves precise control over the therapeutic sequence of "thorough tumor elimination first, followed by bone regeneration activation." This effectively decouples the two functions in temporal and spatial dimensions, ultimately maximizing therapeutic benefits.

These three strategic paradigms clearly outline the field's evolutionary trajectory from simple functional superposition, to efficacy enhancement, and finally to temporal intelligence control (Fig.2).

Future Prospects
Although bifunctional biomaterials demonstrate significant potential in postoperative osteosarcoma management, they still face challenges such as discrepancies between experimental models and clinical reality, insufficient long-term safety validation, and complexities in scaled-up production processes. Future development will place greater emphasis on holistic, personalized, and intelligent material designs, while establishing comprehensive safety evaluation systems and standardized production protocols. With advancing interdisciplinary collaboration, these innovative solutions are expected to successfully transition into clinical practice, ultimately providing osteosarcoma patients with safer and more effective comprehensive treatment options (Fig.3).

Author Biography:
Xie Huiqi is a Researcher, Second-Class Professor at Sichuan University, Doctoral Supervisor, Director of the Stem Cell and Tissue Engineering Research Center at the National Key Laboratory of Biotherapy at West China Hospital of Sichuan University, and Deputy Director of the Orthopedic Research Institute. She also serves as a Principal Investigator at the National Key Laboratory of Biotherapy. She has been appointed as a Distinguished Professor under the "Ministry of Education's Talent Program," an Academic and Technical Leader of Sichuan Province, a Tianfu Science and Technology Leading Talent, a recipient of the inaugural Translational Medicine Innovation Award, and the Chief Scientist of National Key Research and Development Program projects.

With a long-term focus on tissue engineering research, she is dedicated to tissue repair and regeneration, as well as the study and translation of extracellular matrix materials. She has led over 30 national research projects, including key projects and general projects of the National Natural Science Foundation of China, and National Key Research and Development Program projects. As the first or corresponding author, she has published more than 140 academic papers in prestigious journals such as Science Advances, Signal Transduction and Targeted Therapy, Biomaterials, and Bioactive Materials. She has edited one English monograph and contributed to more than ten others. Additionally, she holds over 30 authorized national invention patents.

Under her leadership, her team has successfully translated research outcomes into clinical applications, achieving five Class III medical device product registration certificates from the National Medical Products Administration, with another five currently undergoing multicenter clinical trials. Her research achievements were honored with the First Prize of the 2024 Sichuan Provincial Technological Invention Award.

The complete study is accessible via DOI:10.34133/research.0978