Living photosynthetic micro/nano-platforms: Engineering unicellular algae for biomedical applications

Abstract

The burgeoning field of algal biomedicine capitalizes on evolutionarily refined biological systems to address critical challenges in therapeutic delivery and tissue regeneration. As autotrophic biosystems, unicellular algae uniquely possess multi-functions, including oxygen generation, dynamic motility, fluorescence imaging, and programmable biosynthesis. Their photosynthetic systems not only generate therapeutic oxygen/hydrogen gradients but also facilitate chlorophyll-mediated therapeutics through inherent fluorescence and photodynamic effects. Beyond their metabolic versatility, flagellar propulsion systems, unique morphologies (e.g., helical, elongated), and easily modified surfaces enable precision engineering of algae-based biohybrid microswimmers for spatiotemporally controlled drug delivery. This review comprehensively elucidates mechanistic foundations and biomedical applications of algae-based therapeutic platforms. Spontaneous and persistent oxygen production of algae could rescue hypoxic neurons or cardiomyocytes in myocardial infarction and ischemic stroke lesions, while ameliorating the hypoxia of skin fibroblasts to accelerate wound healing. In addition, increased oxygen levels enable the improvement of hypoxic tumor microenvironments to enhance the sensitivity of chemotherapy/radiotherapy to malignancies. Moreover, many versatile algae-based microswimmers have been developed for delivering therapeutic agents to treat gastrointestinal diseases and bacterial infections. It is believed that these photosynthetic microorganisms have great potential for being developed as next-generation platforms to address growing biomedical challenges.

Keywords: Algae; Drug delivery; Microswimmers; Oxygen generation; Photosynthesis.

Graphical abstract

Scheme 1

Illustration of characteristics, action mechanisms, and various biomedical applications of algae or algae-based biosystems.

Fig. 1

Different morphologies of unicellular algae. (a–g) Typical morphologies and structures observed in various algae, including Spirulina (a), Desmodesmus (b), Synechococcus elongatus (c), Merismopedia punctata (d), Chlorella (e), Phaeodactylum tricornutum (f), and Chlamydomonas (g).

Fig. 2

Schematics of diverse action mechanisms of algae in exerting biomedical functions, such as oxygenating hypoxic tissues, sensitizing chemotherapy/radiotherapy, enhancing the viability of engineered tissues or isolated organs, enabling chlorophyll-based bioimaging and stimuli-driven drug delivery.

Fig. 3

Algae-based biosystems for MI treatment. (a) Cocultured S. elongatus could provide oxygen for cardiomyocytes in an in vitro assay. (b–d) In rodent models of MI, injection of S. elongatus with light irradiation increased tissue oxygenation, maintained myocardial metabolism, and improved cardiac function. Reprinted with permission under a Creative Commons CC BY 4.0 License from Ref. [17]. Copyright 2017 American Association for the Advancement of Science. (e) Schematic illustrations for the mechanisms of UCCy@Gel in treating acute MI. (f) Fluorescence staining image of heat shock protein HSP70. (g) Pro-inflammatory factor expressions in different treatment groups. (h,i) Flow cytometry analysis and immunofluorescence staining results showing the regulation of UCCy@Gel in macrophage polarization. (j,k) UCCy@Gel treatment reduces infarct volumes and promotes myocardial tissue repair. (l) Echocardiography results show that the UCCy@Gel treatment improves the functions of hearts affected by MI. Reprinted with permission from Ref. [20]. Copyright 2022 John Weily and Sons.

Fig. 4

Algae-based biosystems for ischemic stroke therapies. (a) Coculture of C. reinhardtii enhances the functions of isolated cortical slices, which are reflected by the length, frequency, and amplitude of seizure-like event (SLE) activity. The green region indicates periods of algae exposure, while the red region represents periods of non-oxygen inhalation in the upper panel. (b) The yellow region of the upper panel in (a) was enlarged. Reprinted with permission from Ref. [124]. Copyright 2021 Elsevier. (c) Photosynthetic oxygen production of algae in the brain of Xenopus laevis tadpoles. Oxygen concentrations and nerve spiking were tested under light or dark conditions. Reprinted with permission under a Creative Commons CC BY 4.0 License from Ref. [125]. Copyright 2021 Elsevier. (d) Schematic diagram of algae-based nano-photosynthesis therapies for ischemic stroke. (e,f) Cerebral injection of S. elongatus enhances tissue oxygenation of hypoxic brain tissues and decreases neuron apoptosis. (g,h) Fluoro-Jade C staining results demonstrating algae-based therapy reduces the number of degenerating neurons. (i,j) TTC staining results showing algae-based therapy reduces infarct volumes. (k) mNSS, rotarod test, cylinder test, grid test, and pasta test demonstrating behavioral recovery of algae-based therapy. (l) Angiogenesis-promoting effects of S. elongatus were revealed by CD31 immunofluorescence staining. Reprinted with permission from Ref. [19]. Copyright 2021 American Chemical Society.

Fig. 5

Algae-based biosystems for treating gastrointestinal diseases. (a) Schematics of algae motors in a capsule for GI tract delivery. (b,c) The speeds and motile individual proportions of algae motors and Mg motors in simulated intestinal fluids within 12 h. (d) Distribution of algae motor and Mg motor in the gastrointestinal tract. (e) SEM image showing an algae motor loaded with NP(Dox). (f) The speeds of algae-based motors after modification with NP(Dox). (g) Quantification of Dox contents in small intestines treated with the capsules containing Dox-loaded algae or Dox alone. Reprinted with permission under a Creative Commons CC BY 4.0 License from Ref. [33]. Copyright 2022 American Association for the Advancement of Science. (h) Schematic diagram showing the role of algae-MΦNP-robot capsules in treating IBD. (i) Algae-MΦNP-robot capsules decrease the protein levels of inflammation cytokines, including TNF-α, IL-6, IL-1β, and IFN-γ. (j) Representative fluorescence images showing the barrier structures of the colons after being treated with algae-MΦNP-robot capsules. (k,l) Colonic damages were significantly ameliorated after the treatment of algae-MΦNP-robot capsules. Reprinted with permission from Ref. [32]. Copyright 2024 American Association for the Advancement of Science.

Fig. 6

Algae-based drug delivery systems for protecting the gastrointestinal tract from radiation-induced injuries. (a) Schematics of curcumin-loaded algae (SP@curcumin) protecting colon tissues during exerting radiotherapy to colon tumors. (b) Protection of SP@curcumin on intestinal epithelial cells (IEC-6 cells) from radiation-induced damages. (c,d) In vivo assays demonstrating the protective and anti-inflammatory effects of SP@curcumin in X-ray-treated murine models. Reprinted with permission under a Creative Commons CC BY 4.0 License from Ref. [29]. Copyright 2021 American Association for the Advancement of Science. (e,f) Photographs of isolated ceca with tumors showing antitumor therapeutic effects of SP@Curcumin. (g) Schematics of the radioprotective mechanism of Spirulina platensis loaded with amifostine (SP@AMF). (h,i) Radioprotection of SP@AMF on the whole small intestine. (j) Body weight of the mice in indicated groups. (k) Survival curves of mice subject to a fatal dose of abdominal X-ray irradiation. Reprinted with permission under a Creative Commons CC BY 4.0 License from Ref. [27]. Copyright 2022 Springer Science and Business Media LLC; Nature Publishing Group.

Fig. 7

Algae-based biosystems for wound healing. (a) Schematics show the application of the living microecological hydrogel (LMH) for treating hard-to-heal wounds. (b) Dissolved oxygen concentrations in different groups. (c) The effects of Chlorella on the proliferation of B. subtilis. (d,e) Cell viability of L929 fibroblasts subject to hypoxia in different treatments. (f) H&E staining shows the regenerated granulation tissues in different groups (upper panels). Quantification analysis of proportions of wound area (lower-left panel) and granulation tissue thickness (lower-right panel) in indicated groups. Reprinted with permission under a Creative Commons CC BY 4.0 License from Ref. [134]. Copyright 2023 American Association for the Advancement of Science. (g) Schematics of 3D bioprinting algae-based photosynthetic scaffolds for wound healing. (h) The printed photosynthetic scaffolds in different views. (i) Oxygen changes in algae-based photosynthetic scaffolds with various concentrations of algae at 25 °C (left) and 37 °C (right). (j) Representative fluorescent images of human skin fibroblasts stained with hypoxia probe and DAPI. (k) Wound healing processes in indicated groups within 15 days. (l) Quantification of proportions of wound area in (k). (m,n) H&E staining images and quantification results showing the epidermis thickness in different groups. Reprinted with permission under a Creative Commons CC BY 4.0 License from Ref. [136]. Copyright @ 2022 Xiaocheng Wang et al.

Fig. 8

Algae-based biosystem for treating bacterial infections. (a) Schematics of the application of CeCyan-Cu5.4O for the treatment of anaerobic bacterial infections. (b) Evaluation of CeCyan-Cu5.4O for biofilm elimination in vivo. Reprinted with permission under a Creative Commons CC BY 4.0 License from Ref. [152]. Copyright 2022 Elsevier BV. (c) Schematics showing the use of algae-NP-robots for treating bacterial pneumonia. (d) Pseudo-colored SEM images of an algae-NP-robot. (e,f) The speed and the proportion of motile algae-based microrobot in simulated lung fluid at 22 °C, 37 °C, and 40 °C. (g) The distribution of algae-NP-robots in the lung tissues. (h) The in vivo antibacterial efficacy and survival curve results of algae-NP-robots. (i) Representative H&E staining images of the lung tissues of mice treated with algae-NP-robots. Reprinted with permission from Ref. [21]. Copyright 2022 Springer Nature BV.

Fig. 9

Algae-based biosystems for antitumor therapy. (a) Schematics of an algae-based photodynamic therapy for treating triple-negative breast cancer. (b) Representative fluorescence images of tumor section stained with PIMO (hypoxia), MCT-4 (acidity), and SOSG (singlet oxygen). (c–e) Representative images of lung metastatic lesions (c), quantification of tumor volumes (d) and metastatic lesion numbers (e) in different groups. (f) Flow cytometry analysis of DC maturation in isolated tumors in different groups. Reprinted with permission from Ref. [165]. Copyright 2020 John Weily and Sons. (g) Schematics showing the use of an algae-based biohybrid microrobot for treating lung metastatic tumors. (h,i) The speed (h) and motility ratio (i) of these algae-based microrobots at different drug inputs. (j) Snapshot photographs of the self-propelled motion of algae-based microrobots in water over 2 s. (k) Lung distribution of these algae-based microrobots after intratracheal administration. (l) Dox accumulation in the lungs at different time points. (m–o) Tumor bioluminescence intensity (m), survival rates (n), and body weight (o) of mice receiving different treatments. Reprinted with permission under a Creative Commons CC BY 4.0 License from Ref. [170]. Copyright 2024 American Association for the Advancement of Science.