Cancer is a vast concept that refers to a variety of disorders in which the body’s cells grow in an unrestrained manner. There are approximately 200 distinct forms of cancer, and specific cancerous cells can spread to other tissues, creating deadly metastases. Cancer is the most significant cause of mortality worldwide due to population expansion and aging. Because of this substantial degree of impact, cancer treatment has received much interest from the research community (Cooper et al., 2023). According to a report by the UN Health Department, cancer is the leading cause of death worldwide, contributing to nearly 10 million deaths in 2020 or nearly one in six deaths (Siegel et al., 2023). Due to the side effects of existing cancer treatments, it remains challenging to identify more effective therapies, and the development of novel anticancer drugs for anticancer therapy is critical for sustained advancement. It is well known that approximately 60% of hematology and oncology medications come from naturally driven sources, and 33.3% of the most often prescribed drugs are natural substances or derivative products. Because natural solid substances (e.g., polyketides, steroids, phenolic compounds, terpenoids, and antioxidants) have previously been identified in marine species, there has been enormous growth in the research on marine bioactive metabolites (Liu and Qin, 2023).

The method of monitoring and diagnosing diseases by applying nanotech for control is termed “nanomedicine” (Ma and Shi, 2021). Cancer medications that are pharmacologically active reach the tumor tissue with low specificity and dose-limiting toxicity during treatment. Intravenous (IV) and oral routes are two common drug delivery modalities. These approaches have several drawbacks. For example, oral administration of capsules and tablets may result in chaotic pharmacokinetics due to drug exposure to the body’s metabolic pathways. This can lead to the administration of higher-than-necessary doses, which can lead to increased toxicity. Traditional IV approaches are frequently even more difficult. Some traditional intravenous medicines have limited specificity, causing injury to healthy tissues. Nanoparticle-based conjugates are one of the best ways to deliver drugs to target tissues (Kandula et al., 2023).

The photosynthetic microorganisms of marine species, specifically microalgae, can be categorized as eukaryotic (green algae, diatoms) or prokaryotes (blue‒green algae), which are able to produce some of the important compounds of medical interest (Figure 1). Seven marine-derived drugs are available on the marketplace; out of the seven available drugs, four are anticancer drugs. There are nearly 26 marine natural compounds in medical testing, 23 of which exhibit anticancer properties. There are ongoing clinical trials of anticancer drugs produced by green algae (Al-Zahrani et al., 2021). Microalgae produce secondary metabolites, lipid derivatives, carbohydrates, and proteins with various structures. These compounds have been clinically tested, and the results indicate that these conventional treatments strengthen the immune system and assist in cancer elimination (Saadaoui et al., 2020). Halogenated compounds, fatty acids, peptides, steroids, carotenoids, etc., are produced by green algae; these molecules bind at various sites, suppress the mitotic cycle, and cause apoptosis due to cellular pathway activation. In addition to their anticancer effects, these compounds have antioxidant, antimicrobial and anti-inflammatory effects (Ruzik, 2023).

There has been an increase in research in the context of microalgal technologybecause of their rich nutritional bioactive componentsand most importantly, they are renewable, have a high growth rate, require no land, are easily cultivated and harvested, and can grow in all seasons. Some marine species are known to be beneficial health supplements. Antioxidants containing algae are indispensable in cancer therapies. Drugs used in chemotherapy eliminate cancer cells but stimulate the formation of highly reactive partially oxidized compounds called reactive oxygen species (ROS), which have harmful effects. Therefore, antioxidants are given alone or in combination with chemotherapeutics (Ferdous and Yusof, 2021). These antioxidants activate the defense system, prevent genomic instability caused by ROS, and inhibit the proliferation of cells (Abd El-Hack et al., 2019).

The bioactive compounds from microalgae include carotenoids, phycobilin, polyunsaturated fatty acids, polysaccharides, sterols, vitamins, enzymes, and proteins, which have multiple applications in the pharma and cosmetic sectors (Silva et al., 2022). Microalgae produce antioxidant compounds, e.g., microalgal-derived tetraterpenoids, which are antioxidantsthat exhibit antitumor activity (Ferdous et al., 2021). β-Carotene from D. salina has been reported to haveimmunomodulatory and anti-inflammatory effects and is atherapeutic agent for colon, prostate, breast, and lung cancers (Lee et al., 2020). In the cosmetic sector, algal carotenoids are antioxidants, anti-aging agents, and natural pigments (Foo et al., 2021). Algal bioactive compounds, such as α-tocopherol, ascorbic acid, and β-carotene, have shown promising effects on prostate cancer (PC-3) cells through their ability to reduce cell viability and increase reactive oxygen species (ROS) levels and lipid peroxidation (LOP) (Ayna, 2020). Another microalgal bioactive compound, namely, astaxanthin, has shown better antioxidant properties than carotenoids and helps to avoid cell and tissue damage; it is a therapeutic candidate for different malignant cells and has also been reported to act as an anti-aging agent through enhanced aerobic metabolism by preventing protein oxidative decomposition (Faraone et al., 2020; Zhuang et al., 2022).

Microalgae are a potent alternative source for sustainable nanoparticle (NP) synthesis. Low metal concentrations are necessary for microalgal cellular functions such as photosynthetic electron transfer, N₂ assimilation, and cofactors for enzymatic reactions, with the foreseen synthesis parameters affecting their morphology and functions (Hamida et al., 2022; Hamida et al., 2020a; Jacob et al., 2021). Microalgal cells secrete metal chelating agents to mitigate high metal concentration toxicity, which aids in converting metals to nanosized metal nuclei, which is the basis for NP synthesis (Hamida et al., 2020b; Bin-Meferij and Hamida, 2019). Algal metallic NPs of 1–100 nm in size, such as silver (Ag), gold (Au), and platinum (Pt), have been reported to have significant therapeutic efficacy in treating different health ailments, such as cancers (Abed et al., 2022; Xue et al., 2021)), infectious diseases (Lin et al., 2021; Baby and Reji, 2022), and diabetes (Koushki et al., 2021). Microalgal NPs serve as potent candidates in cancer treatment due to their physicochemical properties (small size, large surface area, and surface chemistry), which aid in quickly penetrating cell membranes and organelles toward programmed cell death (Ferdous and Nemmar, 2020). AgNPs have been reported to have promising effects on cancer cells (Nguyen et al., 2021; Haque et al., 2021), with high therapeutic efficacy against MCF-7, Caco-2, HepG2, and HCT-116 malignant cells (Hamida et al., 2020c; Acharya et al., 2022; El-Naggar et al., 2018; Rana and Prajapati, 2023; Sharma et al., 2023; Sharma et al., 2022).

The present review focused on the green synthesis of microalgae-based nanoparticles towards cancer treatment by emphasizing microalgae as a potential for.

NPs are beneficial because they have a large surface area due to their small size (in Nanos), and they can easily cross the cell-tissue barrier to reach their target site. Some natural anticancer drugs, such as camptothecin, may not be used due to their poor solubility, and nanotechnology offers novel solutions to address such difficulties (İnan et al., 2021; Sun et al., 2021). Hydrophobic drugs are encapsulated in nanoparticles, making them soluble; on administration, such drugs are released from the nanoparticle onto the target. Nanoformulations carrying anticancer compounds offer certain advantages, such as better solubility, proper drug accumulation at the target site, enhanced half-life, less toxicity and low cost and stable release of drugs (Heinemann et al., 2021). NPs help bioactive compounds escape the immune system and reach their target to eliminate diseased cells by bypassing biological barriers (Khan et al., 2019).

Several classes of nanoparticles are known, such as (a) carbon-based nanoparticles, which have applications in biomedical fields and biosensors; (b) metal-based NPs, which are used in drug and gene delivery, radiotherapy, and anticancer; (c) polymeric NPs, which are used in biosensors and have environmental and agricultural applications; (d) ceramic NPs, which are used in bone repair; (d) lipid-based NPs, which can overcome biological barriers in the case of cell transfection; and (f) semiconductor NPs, which may have diodes, solar cells, and laser technology applications. The different classes of nanoparticles are depicted in Figure 2.

Biosynthesized nanoparticles such as microalgae-based green synthesized NPs are preferred for cancer treatment becauseof their eco-friendly synthesis without the requirement of high pressures, high temperatures, and toxic chemicals (Khan et al., 2019; Alsammarraie et al., 2018). The microalgae processing for green nanoparticle synthesis consists of microalgal cell cultivation (upstream processing, USP) under stress conditions (Kaushik et al., 2023) and harvesting of microalgal biomass (downstream processing, DSP) (Katiyar and Arora, 2020; Khoo et al., 2020; Tang et al., 2020; Khanra et al., 2018; MatAron et al., 2021). The microalgae-based green synthesized gold nanoparticles (AuNPs) and silver nanoparticles (AgNPs) found to be effective as anticancer agentsthose findings were tabulated in Table1.

Various microalgal species, such as Chlorella, Spirulina, and Scendesmus, were utilized for green synthesis of AgNPs. The process involves the suspending of microalgal biomass in an aqueous silver nitrate solution (1 mM). The synthesized AgNPs were characterized by transmission electron microscopy (TEM), UV spectroscopy, energy dispersive X-ray energy dispersive spectroscopy (EDX) followed by the evaluating the cytotoxicity of the synthesized NPs for anti-cancerous activity (Tran et al., 2023). The green synthesized gold nanoparticles (AuNPs) of D. salina, includes the steps of cultivating the microalgae in MJM media followed by harvesting of microalgal biomass, suspending the aqueous microalgal biomass (20%) in aqueous silver chloride (1 M), and finally centrifuged to get the AuNPs. The green synthesized AuNPs were further characterized by TEM, FTIR, and XPS (Singh et al., 2019).

AgNPs may act against virus-, cancer-, bacteria-, and fungus-infected cells. Muneebaetal (İnan et al., 2021), used the DHM1, DHM3, and DHM3 strains for microalgalNP synthesis to assess their activity against a cancer cell line (MCF7). As a part of the procedure, silver nitrate solution (5mM, aqueous) was added to the microalgae-derived ethanolic extract (5:1). On overnight incubation, a color change was observed from green to yellow and AgNPs were obtained by centrifugation. Sathishkumar et al. (2019) prepared AgNPs from aqueous extract using Trichodesmium erythraeum via an environmentally friendly method that was found to have anti-proliferative and antioxidant properties. Algotiml et al. (2022) biosynthesized nanoparticles from Ulva rigida, Cystoseira myrica, and Gracilaria foliifera and tested them for antimicrobial and anticancer activity. The major algal extract components included fatty acids, amide proteins, terpenoids, flavonoids, polyphenols, fluoro aliphatic compounds, pyruvic acid, volatile compounds, and alkalines. AgNPs exhibited antimicrobial and antifungal activity against foodborne microbes and pathogenic fungi, respectively. These AgNPs were proven to be antidermophytes in the case of skin infections and anticancerous against breast cancer (MCF7) cell lines. Al-Zahrani et al. (2021) synthesized AgNPs by using the microalgae Chaetomorpha ligustica. These compounds were effective against HCT116 and HT29 (colon cancer cell lines) cells. Chaetomoroha ligustica extract and its nanoparticles proved to be cytotoxic, but the cytotoxicity depended on the dose. Several other biosynthesized nanoparticles prepared from Bifurcaria bifurcate, Chlorococcum humicola, Galaxuara elongata, Sargassum plagiophyllum, Amphora-46, Caulerpa racemose, Microcoleus sp., and Ulva fasciata are known for their antibacterial activity (Al-Radadi et al., 2022; Zaman et al., 2020).

Microalgae are used to prepare metallic nanoparticles that have applications in anticancer therapy. Phytochemicals in microalgae contain functional groups such as carboxyl, amino, and hydroxyl groups, which assist in reducing metals and serve as capping agents (providing coatings on nanoparticles). Nanoparticles of silver, cadmium, gold, lead, and silicon-germanium can be prepared using marine species (Restrepo and Villa, 2021). Green nanoparticle formation can be achieved via (a) intracellular synthesis, where compounds inside the cell carry out reduction; or by extracellular synthesis, where compounds outside the cell carry out reduction (Figure 3). In intracellular NPs synthesis, the metal ions taken by microalgal cells are reduced to NPs with the aid of microalgal metabolites, followed by NPs extraction from within the microalgal cells. In contrast, the extracellular NPs synthesis and stabilization proceed with the reduction of metal ions outside the microalgal cells (on the cell surface or algal extracts containing solutions) with the aid of secreted microalgal metabolites. In both approaches, microalgal metabolites/bioactive compounds act as reducing agents (by donating electrons, which reduces the metal ions to NPs synthesis) and capping agents (to stabilize and prevent clumping). The microalgal NPs synthesis also relies on the growth characteristics of microalgae and on the environmental factors (metal ion concentration, pH, temperature, etc.) which dictate the structural and stability features of synthesized NPs for tailored biomedical applications (Restrepo and Villa, 2021).

The bioreduction process includes activation, growth, and termination. For instance, (a) during activation, metal ions are reduced, and reduced metal ions undergo nucleation; (b) during the growth phase, small nanoparticles aggregate into large particles marked with thermodynamic stability; and (c) termination is marked by biomineralization (inorganic (metal)-organic (microalgal assisted) composite) and nanoparticle stabilization (Figure 4). The formation of nanoparticles from Tetraselmisko chinensis and Sargassum muticum occurs via intracellular and extracellular synthesis (Chan et al., 2022). The general procedure for generating microalgal-based nanoparticles includes major steps, viz., (1) the addition of a microalgal extract to a metal ionic solution where the reduction of the metal ion is caused by the functional nature of the microalgal compound; (2) the incubation of the sample after centrifugation, where successful reduction is marked by a change in the color of the solution (e.g., yellow to purple); (3) characterization, where transmission electron microscopy (TEM) reveals the size of the nanoparticles, energy dispersive analysis (EDX) confirms the presence of an element (e.g., silver), Fourier transform infrared (FTIR) spectroscopy reveals the type of biomolecule responsible for the stabilization of the AgNPs, and UV-VIS spectra determine the structure and properties of the nanoparticles (Singh et al., 2019).

Among different microalgae, the selection of microalgal species depends on the gamet of packed biomolecules posses by particular algal species, which dictates the metal ion stabilization towards NPs synthesis, and also on the type of expected metallic NPs with intended application domain. The selection of microalgae for NPs synthesis includes a systematic process of identifying the required metallic NPs for targeted application, with concrete proof of microalgal species for synthesizing particular metallic NPs. Once the type of NPs and microalgal species are identified, growth kinetics and particular metal uptake by selected microalgal species are determined, which follows the optimization of NPs synthesis reaction conditions (temperature, pH, and reaction time) towards better size, shape, and functionality. Finally, the synthesized microalgal NPs have to be characterized to determine the different structural and chemical properties for better suitability for targeted biomedical applications (Arteaga-Castrejón et al., 2024).

Characterization of the NPs was carried out to determine the microscopic structure and material properties through microscopy-, spectroscopy- and X-ray-based techniques (Figure 5). Table 2 highlights the characterization techniques, principles, and use of methods in nanoparticle synthesis and sample preparation.

One of the advanced nanoparticle characterization techniques is nanoSIMS, which uses isotope labeling to analyze and study a complete biological system. It can distinguish between isotopes and combines fine spatial resolution with high atomic sensitivity. The zeta potential, also called the electrokinetic potential, is used to measure the electric charge on the nanoparticle surface. The zeta potential of the particles indicates nanoparticle stability (Fernandes et al., 2023). Other techniques include NMR, which is used to analyze NP size, atomic composition, electronic core structure, ligand density and ligand influence; dynamic light scattering (DLS), which is used to detect agglomerates and hydrodynamic size; SQUID-nanoSQUID, which is used to analyze magnetization remanence, blocking temperature and magnetization saturation; liquidTEM, which is used to study growth mechanisms, depict nanoparticle growth in realtime, superlattice formation and single particle motion; HRTEM, which is used to distinguish amorphous, poly- and monocrystallineNPs; electron diffraction, which is used to study lattice and long-range order parameters; cryo-TEM, which is used to explore aggregation pathways and complete growth mechanisms; electronomography, for 3D particle visualization, video, snapshots, and quantitative information at the atomic scale; electron backscatter diffraction (EBSD), which is used to examine microstructure, texture and defects in NPs; magnetic force microscopy (MFM), which provides information about the magnetic moment of NPs and differentiates them from nonmagnetic NPs (Mourdikoudis et al., 2018).

Microalgae are reservoirs of bioactive compounds such as sterols, polysaccharides, fatty acids, phycobiliproteins, phenolics, and vitamins that play major roles in preventing or curing cancer. Table 3 summarizes the different bioactive molecules produced by microalgae and their therapeutic potential.

The green synthesis of microalgal NPs process starts with the culture of microalgal cells and harvesting. Batch and Fed-batchor continuous cultivation modes are the most common techniques. Biomass is collected and processed during the cultivation phase. The cost of biomass harvesting is estimated to be nearly 30% of the price of microalgal downstream processes. As a result, the high cost of harvesting is one of the most significant bottlenecks in commercializing microalgal processes. Due to the density of microalgal cells during growth, the medium is often low, and most microalgal cells have a negative charge, which causes them to be suspended; moreover, the microalgal harvesting procedure is costly and energy-intensive (Jacob et al., 2021).As a part of harvesting, several harvesting procedures were reported such as sedimentation, ultrasound, centrifugation, filtration, and flotation, to maximize algal biomass yield. Nonetheless, these approaches are not as practical as flocculation because of their high cost and lower efficiency. The flocculation harvesting process is far more comfortable and efficient than previous methods, yet there are still many hurdles to overcome. On the other hand, utilizing flocculants to collect microalgal biomass can pollute slurry concentrates, lowering the market value of algal biomass and making it difficult to isolate valuable microalgal compounds. As a result, the only method to reduce harvesting costs is to improve harvesting technology (Halder and Azad, 2019).

The application of NPs in biomedical applications is the most vulnerable circumstance. The interaction between nanotoxicity and its biomolecules has been the subject of various studies. Nonetheless, assessing and validating nanotoxicity in a living system is complex. The assessment of toxicity and the challenges in identifying the influence on living systems are historic. Researchers face challenges when evaluating nanomaterials in solution-based, powder form and dealing with biological systems using various methodologies for toxicity evaluation. Evaluation tools and characterization procedures are critical for overcoming these hurdles, whereas cytotoxic assays consider nanoparticle shape, size, and morphology (Gupta et al., 2019).

Since the discovery of nanoparticles, physical and chemical production methods have been prominent. In 2009, a wave led to both increases in nanoparticle synthesis and the adoption of biological synthesis methods. There has been an increase in the green synthesis of NPs owing to their sustainability and advantages. By emphasizing the green synthesis of NPs by microalgae, numerous microalgae have been explored for their ability to produce nanoparticles (Bao and Lan, 2019).

Despite their production, what remains unexplored is the application part of synthesized NPs. Research has yet to be carried out to determine their specific role in diagnostics, specifically in diagnosis of cancer. Table 4 summarizes the different clinical application status of green synthesized microalgal NPs. The production of reported microalgal NPs has increased the scope of further research that can focus on exploring the potential uses of these NPs in diagnostics and cancer therapy.

NP use is divided into two primary categories: pharmaceutical and medical. The components and procedures utilized in drug production are subject to quality control. It is crucial to accurately assess formulation excipients and active pharmaceutical ingredients (APIs) for optimizing and evaluating preformulations. To guarantee the safety and efficacy of medications throughout the regulatory timeframe, they must be of sufficient strength, purity, quality, and potency. Many nanostructure systems, such as liposomes, nanoemulsions, dendrimers, nanocrystals, and metal oxides (zinc oxide, superparamagnetic iron oxide, titanium dioxide), have been approved by the FDA. The European Medical Agency and European Commission designated doxorubicin polyisohexylcyanoacrylate nanoparticles for treating hepatocellular carcinoma as orphan drugs and awarded this classification to the Bio Alliance in October 2004. The first nanodrug to receive FDA approval was Doxil in 1995. Dosage forms contain pegylated liposomes that carry the chemotherapeutic drug doxorubicin. An injectable amphotericin liposome is known as an AmBisome^® (Taghizadeh et al., 2021).

There are several requirements for using nanoparticles as drugs, such as size (primary particle size, volume, and surface area), agglomeration state, distribution in two or three dimensions, chemical composition (element identification and distribution, crystal shape, and particle size distribution), and surface composition (charge on the surface). These requirements are crucial for nanoparticles used in biomedical applications. However, specifics of nanoparticle size in bulk materials and intended pharmaceutical items are critical to comprehending a drug’s pharmacodynamics and pharmacokinetic characteristics. There is a clear association between the engineering of nanoparticles, including manufacturing, and their impact on cell surface composition, morphology (size and shape), surface composition, and aggregation. Consequently, for employing green synthesized microalgal NPs for medical usage, more research is needed to ensure that these NPs can pass quality-control examinations. Additionally, essential quality characteristics, including solubility, stability, and solid-state qualities, should be considered when evaluating the suitability of green synthesized microalgal NPs for various pharmaceutical and medicinal applications (Taghizadeh et al., 2021).

To date, only a few nanoparticles of gold and silver have been synthesized using microalgae through green synthesis. The green synthesis of zinc oxide, copper, selenium, titanium, and iron NPs of microalgae and its role in cancer treatment need to be explored. Additionally, numerous microalgae have a high potential for nanoparticle synthesis that remains unexplored. Therefore, microalgal NPs synthesis is a trending field that requires intense research for medicinal applications, especially for cancer treatment.

The microalgal NPs synthesis towards cancer treatment may benefit from further research on the contribution of synthetic biology and genetic engineering approaches. Synthetic biology intrusion enables precise genetic modifications through CRISPR/Cas9 technologies to manipulate the metabolic pathways, which help in the efficient conversion of metal ions into NPs with desired sizes and properties, which eventually help in the cost-effectiveness of the process, which suits the needs of the biomedical industry. The research domain also needs to explore the possibilities of utilizing genetically engineered microalgae for NPs synthesis for cancer treatment towards enhanced efficiencies with tailored NPs producing traits in a sustainable production manner (Zhang and Fussenegger, 2024).

The review discussed the role of microalgal NPs as therapeutic agents for treating cancer cells through a sustainable, green synthesis approach. Furthermore, the probable mechanism of microalgal NP’s synthesis, its characterization approaches, and technical challenges associated with the process have been discussed. Moreover, the extended application of green-synthesized microalgal NPs to cancer cells was addressed through the mechanism of action on cancer cells and cytotoxicity studies. Finally, the quality control aspects and prospects of green-synthesized microalgal NPs are summarized. This review provides a concise overview of the green synthesis of microalgal NPs for potential cancer treatment.