As the global population ages, bone‐related diseases have increasingly become a major social problem threatening human health. Exosomes, as natural cell products, have been used to treat bone‐related diseases due to their superior biocompatibility, biological barrier penetration, and therapeutic effects. Moreover, the modified exosomes exhibit strong bone‐targeting capabilities that may improve efficacy and avoid systemic side effects, demonstrating promising translational potential. However, a review of bone‐targeted exosomes is still lacking. Thus, the recently developed exosomes for bone‐targeting applications in this review are focused. The biogenesis and bone‐targeting regulatory functions of exosomes, the constructive strategies of modified exosomes to improve bone‐targeting, and their therapeutic effects for bone‐related diseases are introduced. By summarizing developments and challenges in bone‐targeted exosomes, It is striven to shed light on the selection of exosome constructive strategies for different bone diseases and highlight their translational potential for future clinical orthopedics.

Bone‐Targeted Exosomes: Strategies and Applications

Rapid and effective repair of injured or diseased bone defects remains a major challenge due to shortages of implants. Smart hydrogels that respond to internal and external stimuli to achieve therapeutic actions in a spatially and temporally controlled manner have recently attracted much attention for bone therapy and regeneration. These hydrogels can be modified by introducing responsive moieties or embedding nanoparticles to increase their capacity for bone repair. Under specific stimuli, smart hydrogels can achieve variable, programmable, and controllable changes on demand to modulate the microenvironment for promoting bone healing. In this review, we highlight the advantages of smart hydrogels and summarize their materials, gelation methods, and properties. Then, we overview the recent advances in developing hydrogels that respond to biochemical signals, electromagnetic energy, and physical stimuli, including single, dual, and multiple types of stimuli, to enable physiological and pathological bone repair by modulating the microenvironment. Then, we discuss the current challenges and future perspectives regarding the clinical translation of smart hydrogels.

Smart Hydrogels for Bone Reconstruction via Modulating the Microenvironment

Osteoporosis (OP), characterized by decreased bone mass and destruction of bone microarchitecture, is the most common bone degenerative disease. Conventional treatments for OP have several side eﬀects, new treatment approaches are needed. Bacterial extracellular vesicles (BEVs) carrying curative molecules have emerged as a promising alternative due to their unique nanosized structures, stable loading capacity, good biocompatibility, ease of modification, and industrialization. In this study, we modified probiotics Escherichia coli Nissle 1917 (ECN) to overexpress hCXCR4 fused with the ClyA on the membrane surface of BEVs. The bone targeted BEVs took advantage of the intrinsic anti-OP function and loaded with SOST siRNA to generate BEVs-hCXCR4-SOST siRNA (BEVs-CSs). The customized BEVs-CSs have exhibited great bone targeting ability without long-term cytotoxicity. In addition, the bioengineered BEVs-CSs can be internalized by bone marrow mesenchymal stem cell and promote their osteogenic differentiation with significant cytocompatibility. Finally, the bifunctional BEVs-CSs successfully reversed the OP in an ovariectomized mouse model. Taken together, such a bioengineered BEVs-based strategy provides an innovative, safe, eﬃcient and promising therapeutic solution for intractable OP treatment. 

Bone-targeted bioengineered bacterial extracellular vesicles delivering siRNA to ameliorate osteoporosis

Microenvironment-responsive nanocarriers for targeted bone disease therapy

Compared to other nanovectors, liposomes exhibit unique advantages, such as good biosafety and high drug-loading capacity. However, slow drug release from conventional liposomes makes most payloads unavailable, restricting the therapeutic efficacy. Therefore, in the last ∼20 years, enzyme-responsive liposomes have been extensively investigated, which liberate drugs under the stimulation of enzymes overexpressed at disease sites. In this review, we elaborate on the research progress on enzyme-responsive liposomes. The involved enzymes mainly include phospholipases, particularly phospholipase A2, matrix metalloproteinases, cathepsins, and esterases. These enzymes can cleave ester bonds or specific peptide sequences incorporated in the liposomes for controlled drug release by disrupting the primary structure of liposomes, detaching protective polyethylene glycol shells, or activating liposome-associated prodrugs. Despite decades of efforts, there are still a lack marketed products of enzyme-responsive liposomes. Therefore, more efforts should be made to improve the safety and effectiveness of enzyme-responsive liposomes and address the issues associated with production scale-up. 

Enzyme-responsive liposomes for controlled drug release

Lipid nanovehicles are currently the most advanced vehicles used for RNA delivery, as demonstrated by the approval of patisiran for amyloidosis therapy in 2018. To illuminate the unique superiority of lipid nanovehicles in RNA delivery, in this review, we first introduce various RNA therapeutics, describe systemic delivery barriers, and explain the lipid components and methods used for lipid nanovehicle preparation. Then, we emphasize crucial advances in lipid nanovehicle design for overcoming barriers to systemic RNA delivery. Finally, the current status and challenges of lipid nanovehicle-based RNA therapeutics in clinical applications are also discussed. Our objective is to provide a comprehensive overview showing how to utilize lipid nanovehicles to overcome multiple barriers to systemic RNA delivery, inspiring the development of more high-performance RNA lipid nanovesicles in the future. 

Lipid nanovehicles overcome barriers to systemic RNA delivery: Lipid components, fabrication methods, and rational design

Chemotherapeutic efficacy for pancreatic cancer is severely compromised by limited drug availability to tumor cells. Herein, we constructed a cancer cell membrane-fused liposome containing a siATG5-loaded calcium phosphate (CaP) core, termed CLip@siATG5. Through cancer cell membrane camouflage, the liposomes evaded immune clearance, actively infiltrated tumor tissues, and were preferentially taken up by homotypic tumor cells. Then, siATG5 escaped from the endosomes and was liberated in the cytoplasm, mainly benefiting from CaP dissolution-induced endosome rupture and liposome disassembly in acidic endosomes. The released siATG5 silenced autophagy protein 5 (ATG5) to inhibit autophagy, starving tumor cells. An alternative nutrient procurement pathway, macropinocytosis, was then upregulated in the cells, leading to increased uptake of the albumin-bound chemotherapeutic agent (nanoparticle albumin-bound paclitaxel (Nab-PTX)). Finally, in a murine pancreatic cancer model, CLip@siATG5 combined with Nab-PTX exerted superior efficacy to a twofold dose of Nab-PTX while avoiding its toxicity. Overall, we justified enhancing chemotherapeutic delivery by modulating the pancreatic cancer cell metabolism, which will enlighten the development of more effective chemotherapeutic adjuvants for pancreatic cancer in the future. 

SiATG5-loaded cancer cell membrane-fused liposomes induced increased uptake of albumin-bound chemotherapeutics in pancreatic cancer cells.

Acid oligopeptide-modified liposomes show promising bone-targeting activity. However, as the modification density of acid oligopeptides increases, liposomes may exhibit stronger hydroxyapatite (HA)-binding activity and decreased blood pharmacokinetics (PK), exerting opposite effects on their bone-targeted delivery. Nowadays, little research has systematically investigated how modification density of acid oligopeptides affects the bone-targeting activity of liposomes. In the present study, we prepared a library of liposomes with identical lipid components and comparable particle sizes but varied modification densities of glutamic hexapeptide (Glu6, a representative of acid oligopeptides). A higher modification density of Glu6 promoted the liposomes binding to HA. In contrast, the high-density Glu6-induced highly negative surface charge stimulated macrophage-mediated phagocytosis of the liposomes, leading to reduced blood retention. Further, biodistribution data revealed that the liposomes with the highest Glu6 density of 5 mol% (5%e-Lip) exerted the strongest bone-targeting activity because their outstanding HA-binding capability completely overcame their reduced blood PK. Moreover, a hemolysis assay showed that the optimized formulation, 5%e-Lip, had good biocompatibility via systemic injection. Overall, these results suggest that the higher modification density of acid oligopeptides facilitated stronger bone-targeting activity of the liposomes, providing a basis for the development of efficient bone-targeting liposomal nanoplatforms for bone disease treatment in the future. 

Optimizing the modification density of acid oligopeptides to enhance the bone-targeting activity of liposomes

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Lipid nanovehicles overcome barriers to systemic RNA delivery: Lipid components, fabrication methods, and rational design

SiATG5-loaded cancer cell membrane-fused liposomes induced increased uptake of albumin-bound chemotherapeutics in pancreatic cancer cells.

Optimizing the modification density of acid oligopeptides to enhance the bone-targeting activity of liposomes