Autogenous healing of osteoporotic fractures is challenging, as the regenerative capacity of bone tissues is impaired by estrogen reduction and existed pro-inflammatory cytokines. In this study, a biofunctional ginsenoside Rg1 and strontium-containing mineral (SrHPO₄, SrP)-incorporated biodegradable silk fibroin-gelatin (SG) scaffold (Rg1/SrP/SG) was developed to stimulate the osteoporotic bone repair. The incorporation of 15 wt% SrP significantly enhanced the mechanical strength, stimulated the osteogenic differentiation of mouse bone marrow mesenchymal stem cells, and suppressed the osteoclastogenesis of RAW264.7 in a concentration-related manner. The loading of Rg1 in SG and 15SrP/SG scaffolds obviously promoted the angiogenesis of human umbilical vein endothelial cells via activating the expression of vascular endothelial growth factor and basic fibroblast growth factor genes and proteins. The bioactive strontium ions (Sr²⁺) and Rg1 released from the scaffolds together mediated lipopolysaccharide-treated macrophages polarizing into M2 type. They downregulated the expression of inflammatory-related genes (interleukin (IL)-1β, tumor necrosis factor α, and IL-6) and stimulated the expression of genes related to anti-inflammation (Arginase and IL-10) as well as bone repair (BMP-2 and PDGF-BB) in the macrophages. The in vivo results also displayed that SrP and Rg1 significantly promoted the bone repair effect of SG scaffolds in osteoporotic critical-sized calvarial defects. Besides, the degradation rate of the scaffolds was close to the bone regeneration rate. Therefore, the simultaneous addition of SrP and Rg1 is a promising way for facilitating the osteoporotic bone repair activity of SG scaffolds via promoting the osteogenesis and angiogenesis, as well as inhibiting the osteoclastogenesis and inflammation.

Degenerative diseases in orthopaedics have become a significant global public health issue with the aging of the population worldwide. The traditional medical interventions, including physical therapy, pharmacological therapy and even surgery, hardly work to modify degenerative progression. Stem cell–based therapy is widely accepted to treat degenerative orthopaedic disease effectively but possesses several limitations, such as the need for strict monitoring of production and storage and the potential risks of tumorigenicity and immune rejection in clinical translation. Furthermore, the ethical issues surrounding the acquisition of embryonic stem cells are also broadly concerned. Exosome-based therapy has rapidly grown in popularity in recent years and is regarded as an ideal alternative to stem cell–based therapy, offering a promise to achieve ‘cell-free’ tissue regeneration. Traditionally, the native exosomes extracted from stem cells are directly injected into the injured site to promote tissue regeneration. Recently, several modified exosome–based strategies were developed to overcome the limitations of native exosomes, which include mainly exogenous molecule loading and exosome delivery through scaffolds. In this paper, a systematic review of the exosome-based strategy for degenerative disease in orthopaedics is presented. Treatment strategies based on the native exosomes are effective but with several disadvantages such as rapid diffusion and insufficient and fluctuating functional contents. The modified exosome–based strategies can better match the requirements of the regeneration in some complex healing processes. Exosome-based strategies hold promise to manage degenerative disease in orthopaedics prior to patients reaching the advanced stage of disease in the future. The timely summary and highlights offered herein could provide a research perspective to promote the development of exosome-based therapy, facilitating the clinical translation of exosomes in orthopaedics. Exosome-based therapy is superior in anti-senescence and anti-inflammatory effects and possesses lower risks of tumorigenicity and immune rejection relative to stem cell–based therapy. Exosome-based therapy is regarded as an ideal alternative to stem cell–based therapy, offering a promise to achieve ‘cell-free’ tissue regeneration.

Photocatalytic therapy holds great prospects in high-performance tumor treatment owing to its advantages of noninvasiveness and oxygen nonreliance. However, there is still a lack of ideal photocatalyst materials that respond to near-infrared (NIR) light, especially with organelle-specific features. Here, a mitochondria-biomimetic organic semiconductor photocatalyst was designed for NIR-activatable photocatalytic immunotherapy of recurrent and metastatic tumor. With biomimetic of mitochondrial membrane, a NIR-responsive conjugated polymer YBSe-SS was prepared into biomimetic nano-photocatalysts (Mito-NPs). Upon NIR-light irradiation, the Mito-NPs achieved effective photocatalytic oxidation of reduced nicotinamide adenine dinucleotide and mitochondria dysfunction, benefiting from the mitochondria-targeted performance. Also, relatively high multiphototheranostics were demonstrated by the Mito-NPs. Subsequently, with Mito-NP–regulated mitochondrial function and metabolism, the in vivo experiments proved that the photocatalytic Mito-NPs combined with immune checkpoint therapy achieved photocatalytic immunotherapy for suppressing primary and pulmonary metastasis of osteosarcoma. This work offers a practical paradigm for NIR-activatable organic photocatalytic materials for high-performance tumor therapy.