Calcium phosphates (CaPs) are ubiquitous in nature and vertebrate bones and teeth, and have high biocompatibility and promising applications in various biomedical fields. Nanostructured calcium phosphates (NCaPs) are recognized as promising nanocarriers for drug/gene/protein delivery owing to their high specific surface area, pH-responsive degradability, high drug/gene/protein loading capacity and sustained release performance. In order to control the structure and surface properties of NCaPs, various biomolecules with high biocompatibility such as nucleic acids, proteins, peptides, liposomes and phosphorus-containing biomolecules are used in the synthesis of NCaPs. Moreover, biomolecules play important roles in the synthesis processes, resulting in the formation of various NCaPs with different sizes and morphologies. At room temperature, biomolecules can play the following roles: (1) acting as a biocompatible organic phase to form biomolecule/CaP hybrid nanostructured materials; (2) serving as a biotemplate for the biomimetic mineralization of NCaPs; (3) acting as a biocompatible modifier to coat the surface of NCaPs, preventing their aggregation and increasing their colloidal stability. Under heating conditions, biomolecules can (1) control the crystallization process of NCaPs by forming biomolecule/CaP nanocomposites before heating; (2) prevent the rapid and disordered growth of NCaPs by chelating with Ca2+ ions to form precursors; (3) provide the phosphorus source for the controlled synthesis of NCaPs by using phosphorus-containing biomolecules. This review focuses on the important roles of biomolecules in the synthesis of NCaPs, which are expected to guide the design and controlled synthesis of NCaPs. Moreover, we will also summarize the biomedical applications of NCaPs in nanomedicine and tissue engineering, and discuss their current research trends and future prospects.

Biomolecule-assisted green synthesis of nanostructured calcium phosphates and their biomedical applications

Biodegradable calcium phosphate nanoparticles for cancer therapy.

Issues caused by maxillofacial tumours involve not only dealing with tumours but also repairing jaw bone defects. In traditional tumour therapy, the systemic toxicity of chemotherapeutic drugs, invasive surgical resection, intractable tumour recurrence, and metastasis are major threats to the patients' lives in the clinic. Fortunately, biomaterial-based intervention can improve the efficiency of tumour treatment and decrease the possibility of recurrence and metastasis, suggesting new promising antitumour therapies. In addition, maxillofacial bone tissue defects caused by tumours and their treatment can negatively affect the physiological and psychological health of patients, and investment in treatment can result in a multitude of burdens to society. Biomaterials are promising options because they have good biocompatibility and bioactive properties for stimulation of bone regeneration. More interestingly, an integrated material regimen that combines tumour therapy with bone repair is a promising treatment option. Herein, we summarized traditional and biomaterial-mediated maxillofacial tumour treatments and analysed biomaterials for bone defect repair. Furthermore, we proposed a promising and superior design of dual-functional biomaterials for simultaneous tumour therapy and bone regeneration to provide a new strategy for managing maxillofacial tumours and improve the quality of life of patients in the future.

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Biomaterial-based strategies for maxillofacial tumour therapy and bone defect regeneration.

Due to a series of systemic and intracellular obstacles in nucleic acid (NA) therapy, including fast degradation in blood, renal clearance, poor cellular uptake, and inefficient endosomal escape, NAs may need delivery methods to transport to the cell nucleus or cytosol to be effective. Advanced nanoscale biotechnology-associated strategies, such as controlling the particle size, charge, drug loading, response to environmental signals, or other physical/chemical properties of delivery carriers, have provided great help for the in vivo and in vitro delivery of NA therapeutics. In this review, we introduce the characteristics of different NA modalities and illustrate how advanced nanoscale biotechnology assists NA therapy. The specific features and challenges of various nanocarriers in clinical and preclinical studies are summarized and discussed. With the help of advanced nanoscale biotechnology, some of the major barriers to the development of NA therapy will eventually be overcome in the near future.

Improved Nucleic Acid Therapy with Advanced Nanoscale Biotechnology

Calcium phosphate (CaP) was engineered as a drug delivery nanocarrier nearly 50 years ago due to its biocompatibility and biodegradability. In recent years, several approaches have been developed for the preparation of size-controllable, stable and multifunctional CaP nanocarriers, and several targeting moieties have also been decorated on the surface of these nanocarriers for active targeting. The CaP nanocarriers have been utilized for loading probes, nucleic acids, anticancer drugs and photosensitizers for cancer imaging, therapy and theranostics. Herein, we reviewed the recent advances in the preparation strategies of CaP nanocarriers and the applications of these nanocarriers in tumor diagnosis, gene delivery, drug delivery and theranostics and finally provided perspectives.

Calcium phosphate nanocarriers for drug delivery to tumors: imaging, therapy and theranostics.

Short interfering RNA (siRNA)-based therapy has a high potential for application in cancer gene therapy. However, delivery of siRNA to target cells is limited by many factors such as serum ribonuclease (RNase) degradation, off-target effects, and inadequate cellular uptake. In this study, an enzyme-response PEG/Lipids/calcium phosphate hybrid delivery system was constructed for siRNA. The nearly neutral charged siRNA@NP2 was resistant to serum-induced degradation. Compared with the non-enzyme-response siRNA@NP1, siRNA@NP2 had efficient delivery in both SMMC-7721 cell lines and SMMC-7721-bearing nude mice. Moreover, safety evaluation of the nanoparticles revealed that they had no significant toxicity both in vitro and in vivo. The developed siRNA@NP2 delivery system presents an efficient tool for siRNA-based cancer gene therapy in vivo.

Tumor Microenvironment-Response Calcium Phosphate Hybrid Nanoparticles Enhanced siRNAs Targeting Tumors InVivo.

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Tumor Microenvironment-Response Calcium Phosphate Hybrid Nanoparticles Enhanced siRNAs Targeting Tumors InVivo.