Algae: A natural active material for biomedical applications

Tremendous opportunities exist for biomaterials in biomedical applications. Microalgae, as a kind of natural resources, have been recently used as novel biological materials, and have attracted a great deal of interest in this field. The unique morphological characteristics and easily functionalized surfaces of microalgae allow the attachment of diagnostic or therapeutic agents on their surface, making them promising candidates for the construction of novel biochemical probes, drug carriers or biomedical scaffolds. As a natural photosynthetic system with rich autofluorescent pigments, algae can improve local oxygen concentration by in situ oxygen production and perform biomedical imaging (fluorescence imaging and photoacoustic imaging), which have been widely studied in the diagnosis and therapies of hypoxia‐associated diseases such as solid tumors and wounds. This review offers a summary of the biological properties of microalgae as well as their recent developments in diagnostic and therapeutic applications in bioanalysis, tissue engineering, hypoxia‐associated tumor therapy and wound healing. This naturally abundant, low cost and biocompatible material offers algae‐based agents an exceptional potential for commercial and clinical practice.


INTRODUCTION
The development of biomaterials is an important research field of modern medicine. Based on their characteristics, biological materials can be classified into four categories: metals, polymers, ceramics and natural materials. Due to the nontoxic, biocompatible and biodegradable requirements of biomaterials, natural products become ideal candidates. [1] The biological investigation of natural materials has been a hot topic in recent years, and S C H E M E 1 Overview of the characteristics and therapeutic functions of microalgae chlorophyll, which could trap light energy from the sun, convert it to chemical energy, and store it as the products of photosynthesis. As their highly efficient photosynthesis, these organisms are considered to be among the fastestgrowing creatures. Therefore, algae are abundant in nature and are considered to be an important source of free oxygen in the atmosphere. [4] At present, algae have been widely used in food, health products and fuel fields due to its rapid growth rate and unique nutritional value. However, the research on the biological applications of algae-based natural active materials is still in the early stages.
Algae species are typically divided into macroalgae and microalgae based on their size and morphology. Macroalgae, or seaweeds, are composed of multiple cells and can be seen without the aid of a microscope. In contrast, microalgae are microscopic photosynthetic organisms, which are more promising for biological applications such as micronano medicine. [5] Therefore, the algae mentioned in the following mostly refer to microalgae. In the past decade, microalgae have been used to promote wound healing, antibacterial, anti-tumor, and so on, with excellent results. More special biological effects and applications of microalgae are being explored.
We firmly believe the biological application of algae will continue to be searched, which may lead to the clinical application of such natural active materials. Therefore, this review article intends to articulate the algae-based biological materials in totality, followed by the recent advances of their biological applications in detail (see scheme 1).

THE MULTIPLE BIOLOGICAL ACTIVITIES OF ALGAE
In general, animals acquire oxygen by respiration and then circulate it throughout the body. Hypoxia is recognized to be associated with many chronic diseases, such as cardiovascular diseases, diabetes, and cancer. [6,7] Thus, reoxygenation became a new strategy for prophylaxis and treatment of these diseases. However, traditional hyperbaric chamber therapy is often lacking in convenience, and conventional oxygen donors could not provide oxygen for the patients sustainably. Therefore, it is an exigence to develop a newly intelligent oxygen delivery system that meets both convenience and continuous oxygen production capacity. Living algae, as a large group of photosynthetic organisms, just happen to meet the requirement for sustainable oxygen delivery under light irradiation. When natural active algae-based biomaterials are transported to the circulatory system or diseased region, the carbon dioxide in the body or the environment can be sustainably converted into oxygen under the light stimuli, providing oxygen to the whole body or lesion site continuously. In the following descriptions, we will discuss the photosynthesis-mediated anti-inflammatory, anti-tumor and other biological applications of algae-based biomaterials in detail.
Photodynamic therapy (PDT) [8] and radiotherapy (RT) [9] are kinds of treatment process which highly depend on oxygen because the production of PDT and RT, reactive oxygen species (ROS), are converted from oxygen. Therefore, living algae are expected to increase the body oxygen content through photosynthesis, providing the source for ROS production, thus increasing the effect of PDT/RT. Moreover, algae are rich in chlorophyll and other photosynthetic pigments, which are a kind of natural photosensitizer for PDT owing to the ROS production upon laser irradiation at 650 nm. [10] That is to say, algae not only can produce the oxygen needed for PDT by photosynthesis, but also have the ability to convert oxygen into ROS by using the natural photosensitizer they contain. Therefore, the therapeutic effect of PDT can be improved by adjusting the light sequence, as will be illustrated in detail later in this article.
Coincidentally, the chlorophyll that algae are rich in can not only be used for photosynthesis and PDT, but also have the ability of fluorescence and photoacoustic imaging. Due to the obvious absorption of chlorophyll at 650 nm, algae-based biomaterials are recognized as potential photoacoustic contrast agents. Meanwhile, as a natural fluorescent pigment, chlorophyll emits red fluorescence at certain excitation wavelength, which was similar to a commonly used fluorescent dye Cy5.5, make algae promising candidates to be used in fluorescence imaging. Combining the photoacoustic/fluorescence imaging ability and therapeutic effect of algae, it is expected to produce more integrated applications of diagnosis and treatment based on algae biomaterials.
In addition to being widely used in food, health products and fuel fields, algae are also primary bio-sorbents involved in the prevention and control of environmental pollution. Algae have a strong adsorption capacity to certain metal ions, micro-molecules and nanoparticles. This adsorption process is not only dependent on electrostatic interactions or physical deposition, but also comprise complex physicochemical and biochemical processes. [11] Therefore, as the natural active materials with strong adsorption capacity, algae can effectively load anticancer drugs, antibiotics and functional nanoparticles for multifunctional algae-based biological systems. Combining the specific properties of drugs or nanoparticles with algae may result in more biomedical applications.
Besides, some algae species with special shape or structure were integrated into biohybrid micro-swimmers for biomedical applications. The various morphologies of algae-based biomaterials affect their steering capabilities and motion control under the applied light or magnetic field. [12] Spirulina, for example, is a microorganism with a natural, intact three-dimensional (3D) spiral morphology, which can be used for creating biohybrid magnetic microrobots. The helical structure endowing it with excellent motion ability, which makes it ideal biomaterials as micro-nano medicine.

Bioanalysis
Nature has endowed microalgae with fine surface structures, including various organic and inorganic microand nano-structures, and complex surface chemistry, making them an attractive candidate for bioimaging and biosensing. Vona et al reported for the first time the in vitro staining of Thalassiosira weissflogii diatoms with a thiophenebenzothiadiazole-thiophene-based fluorophore, to obtain a biohybrid luminescent material with high photoluminescence quantum yields, and applied it to bioimaging. [13] In addition to attaching fluorophores, the shell of microalgae can also bind a highly selective bioprobe such as an antibody, to act as optical biosensors. De Stefano et al chemically modified the frustules of the marine diatom Coscinodiscus wailesii to monitor the molecular recognition event between the antibody and its ligand by fluorescence measurements. [14][15][16] When metal nanoparticles (such as Ag and Au NPs) are modified on the surface of microalgae, an ideal ultrasensitive biosensor can be developed as surfaceenhanced Raman scattering (SERS) substrates for the sensing and identification of substances in trace. Kong et al fabricated hybrid plasmonic-biosilica nanostructures based on diatom photonic crystal biosilica with in situ growth Ag NPs to detect explosive molecules from nanoliter solution. [17,18] Recently, microalgae-based tablets and chips containing Au NPs, as SERS substrates, have been made for chemical composition analysis of sweat and blood samples. [19][20][21][22] Such biohybrid materials use lowcost and environmentally friendly microalgae as template to achieve ultra-high detection limits in medical applications, environmental monitoring, food sensing, and other fields.

Tissue engineering
Although tissue engineering offers unlimited possibilities for regenerative medicine, several problems limit its clinical application. Insufficient oxygen delivery to 3D cultures is considered to be one of the greatest limitations for the effective application of tissue engineering in vitro. [23][24][25] Simultaneously, tissue regeneration relies on necessary nutrients and bioactive molecules to control key biological processes. [26,27] Since photosynthesis is the original source of oxygen for organisms, photosynthetic microalgae present a new way to supply adequate oxygen for tissue engineering. Photosynthetic microalgae Chlamydomonas reinhardtii (C. reinhardtii) have been widely studied in tissue engineering in recent years. Hopfner et al cultured C. reinhardtii in scaffolds for tissue repair, and the microalgae showed high biocompatibility and photosynthetic activity.
In addition, C. reinhardtii could be cocultured with fibroblasts, reducing the hypoxia response of cells under hypoxic culture conditions. Based on the in vitro studies, when the microalgae scaffold was transplanted into a mouse full skin defect, it was found that the microalgae survived for at least 5 days in vivo, and chimeric tissues composed of algae, and mouse cells were formed. [28,29] On this basis, scaffolds constructed by genetically modified microalgae have also been developed, which can also deliver recombinant molecules for gene therapy in addition to basic oxygen supply. Chávez et al created a genetically modified C. reinhardtii that constitutively secreted the human vascular endothelial growth factor VEGF-165 (VEGF) to the wound tissues in vivo. [30] Other algal scaffolds have also been applied in tissue engineering. For instance, Chlorococcum littorale scaffolds could provide enough oxygen to sustain the survival of C2C12 or rat cardiac single-layer cell sheet. [31] Arthrospira scaffolds could improve the adherence and proliferation ability of mesenchymal stem cells from C57/B16N mice liver. [32] Extracts from algae such as polysaccharides have been found to have anti-bacterial, anti-inflammatory, antioxidant, and immunomodulatory properties, so they are widely used as polymer binding agents in bone tissue engineering to help tissue growth and proliferation. [33] Dash et al used methacrylate anhydride-functionalized Ulvan, a polysaccharide sulfate extracted from a green algae called Ulva, to prepare bone scaffolds. Ulvan scaffolds were designed to induce and support enzyme-mediated formation of apatite minerals, in which alkaline phosphataseinduced minerals were added to further enhance the bioactivity. The results showed that the mineralization of biofunctionalized ulvan scaffolds could effectively improve the cellular activity of MC3T3 cells. [34] Pajovich et al conjugated fucoidan (Fuc), a natural polysaccharide derived from brown seaweed algae, and gelatin (Gel) to form templates for the preparation of biomimetic scaffolds for bone tissue regeneration. The scaffolds promoted the proliferation and differentiation of MT3C3-E1 mouse preosteoblasts cells, which indicated the formation of cell-scaffold matrix. [35]

Drug delivery
Microalgae, eukaryotic swimmers with high propulsion (>100 μm/s), phototactic guidance capabilities, and active surface, have been increasingly explored as actuators for cargo delivery. [36,37] Weibel et al employed C. reinhardtii to transport micro-meter scale cargos by using their intrinsic phototaxis mechanism. Cargos attached to microalgae by photocleavage peptides were controlled released under the ultraviolet light irradiation. [38] In addition to phototactic motion control, there have been more and more studies focus on magnetic drive biohybrid microswimmer for targeted cargo delivery. Yasa et al constructed a biocompatible biohybrid microswimmer by attaching polyelectrolyte-functionalized magnetic spherical cargoes (1 μm in diameter) to the surface of C. reinhardtii through non-covalent interaction. Under the control of magnetic field, the biohybrid algal microswimmers could effectively deliver fluorescent isothiocyanate-dextran (a water-soluble polysaccharide) molecules to mammalian cells. [39] Based on this, microalgal cargo-carrying systems provide a new platform for the application of targeted drug delivery in biomedicine, such as allowing delivery of chemotherapy drugs to tumor cells. Akolpoglu et al modified C. reinhardtii with chitosan-coated iron oxide nanoparticles (CSIONPs), wherein CSIONPs were conjugated with chemotherapy drug doxorubicin (DOX) by a photocleavable linker. In vitro cell coculture experiments showed high uptake of DOX molecules by the SK-BR-3 cancer cells upon a light-stimuli. [40] Wang et al used Spirulina (Sp.) as biotemplate to fabricate biohybrid (Pd@Au)/Fe 3 O 4 @Sp.-DOX microrobots (Figure 1), in which Pd@Au NPs were used as photothermal conversion agents, and Fe 3 O 4 enabled the magnetic actuating ability. The magnetic microrobots showed excellent synergistic chemo-photothermal therapeutic efficacy for both 769-P and EC109 cancer cells. [41] Most of the algae-based targeted drug delivery systems have been carried out in vitro, and only a few have emerged recently to focus on the in vivo studies. Delalat et al genetically engineered diatom Thalassiosira pseudonana in vivo to display an IgG-binding domain of protein G on the biosilica surface. This in vivo modification was followed by attachment cell-targeting antibodies (Ab) and chemotherapeutic drug molecules (camptothecin and 7-ethyl-10-hydroxy-camptothecin) to the surface of the diatom-based biosilica. Genetically engineered biosilica frustules selectively targeted and killed neuroblastoma and B-lymphoma cells in vitro and reduced tumor growth in a SH-SY5Y neuroblastoma tumor-bearing mouse model in vivo. [42] Instead of using derivatives of algae, a possible and economical for in vivo targeted drug delivery can be achieved by algal biomass itself. Zhong et al used Spirulina platensis (S. platensis) as drug carriers to fabricate a DOX-loaded system for lung-targeted delivery (Figure 2). In this system, positively charged DOX molecules were firstly loaded to negatively charged S. platensis (SP) by noncovalent electrostatic interactions. Moreover, drug loading efficacy was further improved as small DOX molecules were allowed to enter the cell envelope through the continuous water channels and junctional pores (14-16 nm) on the SP cell membrane. The micrometer-sized and spiralshaped SP carriers were easily trapped by pulmonary capillaries, allowing them to passively target the lungs. The fabricated DOX-loaded SP (SP@DOX) system exhibited obvious killing ability to 4T1 and CT26 tumor cells in vitro. Subsequently, the targeted chemotherapeutic efficacy of SP@DOX was confirmed in a 4T1 breast cancer mouse model of lung metastasis. [43]

Hypoxia-associated tumor therapy
Tumor hypoxia is a common feature of the solid tumors induced by rapid growth and abnormal angiogenesis, which largely results in the resistance of tumor cells to various oxygen-dependent cancer therapies, such as RT and PDT. [44,45] Thus, improving the oxygen concentration in hypoxic tumors should substantially enhance the therapeutic effect of relevant therapies. Very recently, microalgae, including spirulina and chlorella, have been utilized as oxygenerator for in situ O 2 generations based on the -DOX microrobots mediated targeted delivery of DOX to 769-P cells. [41] Copyright 2019, American Chemical Society specific photosynthesis to alleviate tumor hypoxia, which has been further explored in vivo for enhanced tumor therapies, including RT, PDT, or RT/PDT synergistic therapies. Zhong et al proposed a cancer-targeted theranostic strategy based on a photosynthetic biohybrid microswimmers system (Figure 3), in which S. platensis was engineered with superparamagnetic magnetite (Fe 3 O 4 NPs). [46] The magnetic S. platensis (MSP) could magnetically target to the tumor site under an external magnetic field and generate O 2 in situ to improve the local O 2 concentration in the tumor, so as to realize an enhanced RT on 4T1 tumorbearing mouse model. Furthermore, chlorophyll released from algae could be used as photosensitizer for successive PDT, which greatly promoted the anticancer effect by synergistic RT/PDT treatment. Importantly, these MSP exhibited the capability of fluorescence and photoacoustic imaging based on chlorophyll and magnetic resonance imaging based on Fe 3 O 4 NPs to potentially monitor the tumortherapeutic procedure by such tri-modality imaging.
In contrast, chlorella, a much smaller algae, has also been widely studied as a highly efficient oxygen-generating agent for the treatment of hypoxic-associated cancer. Zhou et al reported an autotrophic light-triggered green affording oxygen engine (ALGAE) system, which was composed of Chlorella pyrenoidosa and calcium alginate, achieving nearly three times oxygen production compared to inorganic oxygen production materials. The calcium alginate in this system could prevent the chlorella from the phagocytosis of macrophage, making a long period for oxygenaffording in vivo for the repeated PDT. The ALGAE were implanted around the tumors of 4T1 tumor-bearing mice in a minimally invasive way to stay a long period around the tumor tissues for affording sufficient oxygen. The hypoxia-resistant PDT induced by ALGAE, not only effectively ablated tumor tissues but also successfully inhibited tumor progression and metastasis. [47] To resolve the tumor-targeting issue and maintain the oxygen-producing activity in vivo, a series of surface modifications have Significance of differences was determined using two-sided Student's t-test. ***p < 0.001 [43] Copyright 2020, John Wiley and Sons been applied to chlorella for intravenous injection. Li et al reported a biohybrid Algae@SiO 2 system (Figure 4), by modifying the Chlorella vulgaris (C. vulgaris) with silica by a one-step biomimetic silicification method. As a protective shell, the SiO 2 layer outside the algae could significantly reduce the cytotoxicity and improve their tolerance and bioactivity in the tumor area. Algae@SiO 2 could reach the tumor site and mediate RT and PDT combined therapy to inhibit tumor growth in 4T1 tumor-bearing mice after intravenous administration, indicating their high bioactivity in vivo. [10] Qiao et al recently modified the surface of C. vulgaris with red blood cell membrane (RBCM) to protect it from the clearance from many mononuclear phagocyte system organs (Figure 4). The RBCM-engineered algae (RBCM-algae) showed greater stability and higher tumor uptake than unmodified native algae. With the aid of Xray and 650 nm laser irradiation, RBCM-algae significantly suppressed the tumor growth in both 4T1 breast tumor and SKOV3 ovarian tumor mouse models, attributing to the enhanced radiosensitizing and photodynamic effect. In addition, relevant molecular mechanism underlying RBCM-algae-mediated abrogation of hypoxia-dependent radioresistance was also elucidated to further verify the reliability of algal therapy for hypoxic tumors. They found orthotopic breast tumor model. Significance of differences was determined using two-sided Student's t-test. ***p < 0.001 [46] Copyright 2020, John Wiley and Sons that the combination of RBCM-algae + RT + laser therapy resulted in tumor regression, by inhibiting angiogenesis and proliferation and inducing apoptosis, including the down-regulation of HIF1α and VEGF levels, followed by remarkable decrease of CD31 and Ki67 expression and increase of cleaved Caspase3. [48] These findings provide proof-of-concept evidence for the future development of algae-mediated hypoxic-associated tumor therapy.

Wound healing
Wound healing is a complicated process, in which oxygen as a crucial molecule participates in cell metabolism, signaling, and many reparative activities, like cell proliferation, collagen synthesis, re-epithelialization, and anti-bacterial immune response. [49][50][51] However, vascular disruption and vasoconstriction lead to insufficient oxygen supply, inducing a hypoxic tissue, which is unfavorable for the healing process. [52,53] Therefore, increasing the oxygen supply to the hypoxic tissues has become an effective strategy to promote wound healing. Herein, microalgal treat-ment seems to be a promising therapeutic approach that provides oxygen to wound areas for regenerative therapies. Li et al developed an algal hydrogel (SP gel) composed of S. platensis and natural polymer carboxymethyl chitosan, which could simultaneously maintain the oxygen production capacity of algae and promote their adhesion to the infected wound ( Figure 5). Moreover, SP gel could generate ROS by the released chlorophyll from algae under a 650 nm laser irradiation, thus photodynamic killing bacteria in the infected area. SP gel combined with the laser irradiation treatment showed strong in vitro antibacterial activities against two representative strains gram-positive Staphylococcus aureus (S. aureus) and gram-negative Escherichia coli (E. coli). In the S. aureus-infected mouse model, SP gel + laser group showed better wound recovery than the other groups, demonstrating the excellent wound healing effects of SP gel-mediated PDT. [54] Besides, algae-gel has also been studied to treat wounds that are more difficult to recover, such as chronic wounds in diabetes. Chen et al reported a patch-like wound dressing named alga-gel patch (AGP), in which the filled gel beads contained bioactive Synechococcus elongatus F I G U R E 4 (A) The schematic illustration of the biomineralization process for preparing Algae@SiO 2 and Algae@SiO 2 -mediated tumor treatments. [10] Copyright 2020, American Chemical Society. (B) The schematic illustration of RBCM-algae as an oxygen source for the treatment of hypoxic tumors in combination with radiotherapy and photodynamic therapy. (C) RBCM-engineered algae could efficiently reach the tumor site after intravenous injection. (D) RBCM-algae mediated enhanced RT and PDT efficiently inhibited the tumor growth in 4T1 tumor-bearing mouse model. Treatments: 1, control; 2, laser alone; 3, RBCM-Algae alone; 4, x-ray irradiation (RT) alone; 5, RT + laser; 6, RBCM-Algae + laser; 7, RBCM-Algae + RT; and 8, RBCM-Algae + RT + laser. (E) Possible mechanism of the RBCM-algae mediated tumor treatments. Significance of differences was determined using two-sided Student's t-test. ***p < 0.001. [48] Copyright 2020, American Association for the Advancement of Science (S. elongatus) PCC7942, ensuring the dissolved oxygen delivery to the wound site. AGPs could produce continuous oxygen, effectively penetrate the skin, and were effective in various hypoxic chronic wounds. Notably, PCC79422 might contain growth factors that further stimulated cell proliferation and migration for promoting wound healing. [55] In addition to being used as wound dressings and patches, microalgae can also be incorporated into surgical sutures to improve healing capacities. Cerdas et al seeded C. reinhardtii in polyglactin sutures to fabricate the photosynthetic sutures ( Figure 6). In addition to possessing basic functional like mechanical fixation, they were capable of locally and stably releasing oxygen and recombinant human growth factor (VEGF, platelet derived growth factor (PDGF-BB), or stromal cell-derived factor 1A (SDF-1A)) at the wound site. [56] These algal agents have demonstrated their feasibility for commercial and clinical use in wound healing. Compared with other groups, SP gel + laser group showed the best wound closure and the least degree of hypoxia at the wound area. Significance of differences was determined using two-sided Student's t-test. *p < 0.05, ***p < 0.001. [54] Copyright 2020, John Wiley and Sons

In vitro toxicity
Caco-2, HT-29, and HT-116, even at a concentration of up to 1000 μg/mL. [57] In addition, chlorella has also been shown to be low-toxic to many normal cells lines, including fibroblast, Jurkat T cells, HEK293 kidney cells. [10,48] Multiple studies have demonstrated the low cytotoxicity of spirulina on various cancer cell lines (SKOV3 ovarian cancer cells, 4T1 breast cancer cells, and CT26 colon cancer cells) and normal cell lines (HEK293 kidney cells, Hepl hepatocyte cells, epithelial cells, and HaCaT cells). [46,54] Interestingly, Yan et al found that magnetic S. platensis was nontoxic to normal cells (3T3 fibroblast cells), even at high concentrations, but showed a significant cytotoxicity to cancer cells, especially for SiHa cervical cancer cells. After ruling out the effects of the Fe 3 O 4 NPs coating, they concluded that the most likely cause of SiHa cell apoptosis was the interaction between the cancer cell membrane and certain active substances released from the algae. [58]

In vivo toxicity
As discussed above, surface modification and engineering of algae can be carried out by means of biomineralization, cell membranes or nanoparticles coating, polymer crosslinking, etc., so as to reduce the systemic toxicity of algae applied in vivo while ensuring their biological activity. Schenck et al found that when microalgae-fibrin dressing The color change and photosynthetic ability of C. reinhardtii after seeding into the threads, showing their excellent biocompatibility. [56] Copyright 2018, Elsevier wound was implanted in a mouse full skin defect, it did not trigger systemic inflammatory effects, including no significant changes in spleen and lymph nodes weight, and levels of immunoglobulin M (IgM), G (IgG), and 40 inflammatory cytokines. [29] Next, the long-term effects of intravenous injection administration on mice have also been studied. Studies by Zhong et al showed that after 30 or even 60 days of intravenous injection of the bare or magnetic spirulina, the main organs of the treated mice still remained normal tissue structures without obvious inflammatory lesions or damage. They also investigated the metabolism behavior of these algal agents after intravenous injection and found that algae could be degraded and excreted out via the renal-urinary system, indicating their clearance properties in vivo. [43,46]

CONCLUSION
This review aims to present a comprehensive view of the classification, characteristics and therapeutic functions of algae from a broad perspective. The main focus is directed toward recent progress in the biological applications of microalgae, especially for bioanalysis, tissue engineering, drug delivery, tumor therapy, and wound healing in vitro and in vivo. As one kind of most well-sourced organisms in nature, microalgae make the manufacture of algal agents (algal scaffolds, algal carriers, algal patches, etc.,) especially simple and low in cost. Also worth mentioning are the oxygen-producing and autofluorescence characteristics of microalgae, which pave a new strategy for the diagnosis and treatment of hypoxia-associated diseases. Various studies have demonstrated the certain biocompatibility and low toxicity of the commonly used algae both in vitro and in vivo. Nevertheless, the use of algae for biomedical purposes requires more detailed investigations, including further studies in other clinically relevant animal models, such as non-human primates, to assess the safety and efficacy of these algal agents in clinical applications. In conclusion, microalgae are great candidates for the design of a new era of biomedical materials, although they are still in their early stage of research, leaving room for further exploration and improvement.

A C K N O W L E D G M E N T S
This work was supported by the National Natural Science Foundation of China (No. 81971667).

C O N F L I C T O F I N T E R E S T
The authors declare no conflict of interest.