深空环境赋能药物设计与开发（英文）

Deep space environment empowering drug design and development

摘要

深空特有的微重力、宇宙辐射与极端环境，正逐渐成为推动药物创新的重要驱动力。这些独特因素为优化药物剂型、提升晶体结构质量及加速疾病治疗靶点的发现提供了新路径。深空研究的进展不仅有助于突破地面药物开发的关键瓶颈，还可推动基于结构的药物设计进展，加深人们对环境应激下细胞响应机制的理解。目前，深空药物开发的进展主要包括基于微重力探索疾病机制、基于微重力的蛋白质结晶及基于深空辐射和深空资源的药物开发。然而，实验条件受限、高昂成本及数据可重复性不足等问题是目前限制其广泛应用的关键挑战。未来，随着自动化技术、人工智能分析和在轨制造等新兴技术的融合应用，深空药物开发有望实现更高的规模化与精准化，从而开辟生物制药科学的新前沿。

Abstract

The unique characteristics of the deep space environment, microgravity, cosmic radiation, and extreme temperature fluctuations, are emerging as major driving forces for pharmaceutical innovation. These factors provide new avenues for optimizing drug formulations, improving crystal structure quality, and accelerating the discovery of therapeutic targets. Advances in deep space research not only help overcome critical bottlenecks in terrestrial drug development but also promote progress in structure-based drug design and deepen understanding of cellular stress-response mechanisms. Current progress in space-based pharmaceutical research primarily includes the study of disease mechanisms under microgravity, protein crystallization in microgravity, and drug development utilizing deep space radiation and resources. However, the operational complexity, high costs, and limited data reproducibility of space experiments remain key challenges hindering widespread application. Looking ahead, with the integration of automation, artificial intelligence analysis, and on-orbit manufacturing, deep space drug development is expected to achieve greater scalability and precision, opening a new frontier in biopharmaceutical science.

Graphical abstract

关键词

药物开发 / 深空环境 / 微重力 / 蛋白质结晶 / 辐射

Key words

drug development / deep space environment / microgravity / protein crystallization / radiation

The journey into space, from Yuri Gagarin’s historic 108-minute orbital flight in 1961 to Valeri Polyakov’s 437-day mission aboard Mir, has consistently highlighted profound physiological challenges inherent to the space environment^[1]. While the International Space Station (ISS) maintains approximately 89% of Earth’s gravitational force (9.81 m/s²), astronauts experience sustained microgravity due to free-fall dynamics. This unique condition can decouple tissue responses, as demonstrated by the LunHab project^[2], where lunar simulation induced leg muscle atrophy without accompanying bone loss. Such paradoxical observations underscore the urgent need to address systemic declines in muscle mass, immune function, and cardiovascular health, issues that persist even among rigorously conditioned astronauts adhering to advanced exercise regimens like high-intensity interval training^[3]. With ambitious plans for very long-duration missions (vLDMs) (>1 year) to Mars, the inherent limitations of terrestrial pharmaceuticals—including degradation under cosmic radiation, shelf-life constraints, and suboptimal efficacy in microgravity—demand transformative solutions^[4].

Excitingly, the specialized space environment, characterized by microgravity, ionizing radiation, extreme thermal and pressure conditions, and unique resource constraints, simultaneously offers unprecedented opportunities to reimagine drug discovery. The global pharmaceutical sector, currently burdened by declining productivity and soaring development costs (averaging $2.6 billion per approved drug), stands to benefit significantly from innovations catalyzed by space-based research^[5]. For example, microgravity allows protein crystallization at exceptionally high resolutions, expediting structural elucidation and target validation for complex diseases such as cancer and neurodegeneration^[6]. Although radiation can compromise drug stability, it also provides a high-throughput platform for screening radioprotective compounds and mutagenic libraries^[7]. In parallel, artificial intelligence (AI) platforms can design molecules with optimized lipophilicity, potency, and radioprotective pharmacophores, may harness space-derived biological data to overcome traditional bottlenecks in lead optimization^[8]. Furthermore, microbial cultures grown in microgravity exhibit enhanced secondary metabolite production, offering promising avenues to revitalize stagnant antibiotic development pipelines.

This perspective outlines how space environments simultaneously challenge human physiology and catalyze pharmaceutical breakthroughs. We will explore microgravity’s role in unraveling novel disease mechanisms, radiation’s dual threat and utility, and the imperative for stable formulations in resource-limited settings. By bridging insights from terrestrial analogues, AI-driven drug design, and spaceborne biotechnology, we aim to highlight critical synergies between extraterrestrial research and terrestrial medicine. This review advocates for a paradigm shift in therapeutic development, essential for supporting both interplanetary exploration and advancing global health.

1 Characteristics of the deep space environment

The unique and extreme characteristics of the deep space environment present a dual nature of challenges and opportunities for human exploration. For drug development, this environment functions as both a “natural laboratory” and a “resource bank”. Its microgravity, radiation, extreme conditions, and unique resources offer unparalleled opportunities for studying disease mechanisms, advancing drug delivery technologies, developing novel compounds, and constructing comprehensive space medical systems (Figure 1). The synergistic integration of space biology, synthetic biology, and material science is poised to vigorously propel breakthroughs in the emerging field of “space medicine”.

1.1 Microgravity

Microgravity, a defining characteristic of the deep space environment, offers an unparalleled setting for advancing drug discovery and preparation. The near-absence of gravity significantly reduces molecular settling and convection in liquid media, thereby facilitating a more orderly arrangement of molecules during crystallization. This leads to the formation of larger and more highly ordered crystals^[6]. Such enhanced crystallization not only aids in the preparation of high-quality biomolecule drugs (e.g., proteins, nucleic acids) but also improves the resolution of drug target structures (e.g., membrane proteins, viral proteins), thereby accelerating structure-based drug design (SBDD)^[9]. Furthermore, the microgravity environment promotes cellular growth in configurations closely resembling their in vivo three-dimensional structures. This enables the formation of more realistic disease models (e.g., tumor spheroids, organoids), enhancing the accuracy of drug screening and reducing reliance on animal experimentation^[10]. For biological organisms, microgravity can accelerate or simulate certain disease-related physiological changes (e.g., osteoporosis, muscle atrophy), which is beneficial for rapidly establishing relevant disease models^[11]. However, it is crucial to note that experimental results obtained in microgravity must be rigorously confirmed and compared with ground-based conditions, as differences between the 2 environments may exist.

1.2 Radiation

The deep space radiation environment is predominantly characterized by galactic cosmic rays (GCRs) and solar energetic particles (SEPs), which are significantly more intense than those in near-Earth orbits (NEOs) due to the lack of protective shielding from Earth’s magnetosphere. GCRs, composed of high-energy protons and heavy nuclei, can penetrate spacecraft shielding, inducing single-particle effects in electronic devices and causing DNA damage in biological organisms, thereby elevating astronauts’ cancer risk. SEPs, closely associated with solar activity, can result in sudden and extreme spikes in radiation exposure, increasing doses by up to a hundredfold during an outburst. This high-radiation environment presents a dual role in drug discovery. On the one hand, excessive radiation can induce biological effects through direct energy deposition in biomolecules (proteins and nucleic acids) or indirectly via interactions with radiation-induced free radicals, potentially leading to mutations and affecting experimental outcomes^[7]. On the other hand, such high-radiation environments can accelerate mutation studies, facilitating the screening of microorganisms for high-yielding or novel metabolites. These specific metabolites or enzymes (e.g., DNA repair enzymes) may then be harnessed for biopharmaceutical applications or industrial enzyme production^[12]. Furthermore, radiation protection is an integral aspect of drug development. Radiation-induced DNA damage can effectively mimic cancer or aging-related lesions, providing valuable models for the development of radioprotective agents (e.g., anti-oxidants, DNA repair enhancers)^[13].

1.3 Extreme environments

Beyond radiation and microgravity, deep space is characterized by multiple extreme environmental conditions. In the absence of atmospheric regulation, spacecraft experience temperature variations of hundreds of degrees Celsius, ranging from a maximum of 121 ℃ on the sun-exposed side to a minimum approaching absolute zero (-273.15 ℃) in the shade. Such extreme temperatures can compromise the molecular structure of drugs, necessitating advanced formulation technologies and the development of temperature-resistant materials (e.g., liposomes, polymer nanoparticles) or lyophilized formulations^[14]. Furthermore, the vacuum environment inherent to deep space can facilitate the loss of volatile drug components, demanding improvements in encapsulation processes^[13]. At the same time, these extreme conditions offer unique advantages. The high vacuum and ultra-clean environments of deep space are conducive to maintaining high purity during drug production. Similarly, the prevailing extremely low temperatures and microgravity conditions favor the development of more stable and uniform drug formulations, including advanced nanomedicines^[15]. Moreover, the potential discovery or engineering of extremophilic microorganisms (e.g., barophilic, psychrophilic, thermophilic) adapted to space conditions may reveal novel metabolic pathways and produce specialized enzymes or bioactive compounds, such as heat-stable enzymes and antioxidants. These discoveries hold promise for drug synthesis and the development of innovative therapeutics^[16].

1.4 Special resources

The deep space environment offers unique and potentially transformative resources, many of which are exceedingly scarce on Earth. These extraterrestrial materials present unprecedented opportunities for revolutionary breakthroughs in drug development, ranging from novel raw materials to entirely new therapeutic approaches. For instance, lunar regolith, rich in helium-3 isotopes, could be harnessed for safer, more precisely targeted radiation therapies and advanced radioactive tracers^[17]. Beyond the Moon, asteroids and meteorite fragments contain rare earth elements, such as neodymium and europium, which could serve as novel catalysts for drug synthesis or enhance the performance of advanced imaging agents, including MRI contrast agents^[18]. Perhaps most intriguing is the potential discovery of specialized biomolecules in extraterrestrial samples. The identification of non-terrestrial amino acids or lipids, for example, could fundamentally expand our understanding of biological chemistry, revealing entirely new drug targets and paving the way for innovative biomimetic materials with unprecedented therapeutic or drug delivery capabilities. The integration of these unique space-derived resources thus represents a frontier with the potential to fundamentally reshape the landscape of biopharmaceutical science^[19].

2 Advances in deep space drug development

With the continuous advancement of space life sciences and aerospace technology, the extreme environments of space are rapidly transforming into a “super accelerator” for drug development. Unique space characteristics such as microgravity, intense radiation, and ultra-high vacuum complement Earth-based laboratory environments, providing unprecedented experimental conditions for novel drug discovery and mechanistic research. This evolution is propelling space-based pharmaceuticals from an early stage of experimental exploration toward a new phase of industrial application^[20].

2.1 Exploring disease mechanisms based on microgravity

Microgravity, a defining feature of the deep space environment, induces systematic changes in cellular morphology, cytoskeletal structure, signal transduction, and gene expression. This provides an unparalleled perspective for investigating the mechanisms underlying major diseases, particularly those affecting the musculoskeletal system^[21]. Microgravity exposure affects bone metabolism, reducing the osteogenic differentiation potential of mesenchymal stem cells (MSCs), as well as the expression of several bone biomarkers^[21]. Muscle metabolism is also affected by microgravity exposure. A reduction in the regenerative capacity of satellite cells results in a decrease in myogenesis (Figure 2). For instance, a seminal study by Professor Rando’s team at Stanford University, involving human muscle tissue cultivated on the International Space Station National Laboratory (ISSNL), revealed profound metabolic imbalances^[22]. Transcriptomic and proteomic analyses demonstrated that just 7 days of microgravity exposure led to decreased expression of mitochondrial function genes and increased lipid synthesis gene expression in muscle tissues. This metabolic shift is highly consistent with the pathological manifestations of age-related sarcopenia^[22]. Crucially, the study also identified that regenerative drugs, such as insulin-like growth factor-1 (IGF-1) and 15-hydroxyprostaglandin dehydrogenase inhibitor (15-PGDH-i), could partially reverse these adverse effects, thereby pinpointing potential therapeutic targets for microgravity-related muscle conditions.

The unique microgravity environment is equally invaluable for elucidating the mechanisms of bone loss, a phenomenon closely mirroring terrestrial osteoporosis. Astronauts consistently experience an average bone loss of 0.5% to 2.0% per month during spaceflight, with weight-bearing bones (e.g., calcaneus, tibia, femur, and vertebrae) showing significantly greater loss than non-weight-bearing bones. Alarmingly, bone recovery typically lasts two to three times longer than the mission duration, and complete restoration may not always be achievable. This bone loss primarily stems from microgravity inhibiting osteoblast differentiation and enhancing osteoclast activity, leading to a critical imbalance in bone metabolism^[23]. Ground-based research has extensively utilized mouse hindlimb unloading models to simulate microgravity, significantly advancing our understanding of drug intervention mechanisms^[24-25]. For example, Wang, et al^[26] demonstrated that simulated microgravity induces osteoblast pyroptosis via the NOD-like receptor family pyrin domain containing 3 (NLRP3)-caspase-1 signaling axis, thereby inhibiting bone formation. Importantly, NLRP3 inhibitors (e.g., MCC950) substantially restored osteogenic activity. Similarly, Shi, et al^[27] showed that inhibiting mitochondrial fission improved osteoblast energy metabolism under simulated microgravity, reversing osteogenesis disorders and supporting mitochondrial dynamics as an intervention strategy. With increased accessibility to spacecraft platforms, some research teams^[28-29] have begun directly evaluating candidate drugs in actual space environments to assess their efficacy. These collective findings emphasize that microgravity serves not only as an accelerated platform for disease modeling but also as an unprecedented opportunity for novel target discovery and drug development. The mechanisms underpinning microgravity-induced bone metabolic disorders are progressively being elucidated, promising innovative drug development targeting pathways like pyroptosis and mitochondrial function. This offers crucial new solutions in space medicine for osteoporosis, a prevalent global chronic disease.

Beyond musculoskeletal issues, the unique physical effects of microgravity in deep space hold profound significance for studying the pathology of neurodegenerative diseases. Early studies^[30-33] have investigated microgravity’s impact on neurochemicals, focusing on dopamine (DA), 5-hydroxytryptamine (5-HT), and related neurotrophic factors. Such research not only provides crucial insights into spaceflight’s effects on the brain but also opens innovative avenues for developing therapeutic drugs for neurodegenerative conditions. The 2013 Bion-M1 biosatellite mission, for instance, revealed that prolonged spaceflight downregulates key enzymes [e.g., tyrosine hydroxylase (TH), monoamine oxidase A (MAOA), catechol-O-methyltransferase (COMT)] involved in DA synthesis and degradation. This leads to reduced dopamine synthesis and slowed degradation, consequently affecting neural circuitry and cortical motor information transmission^[34]. Popova, et al^[35] further observed that deep space microgravity can elevate cortisol levels, decrease tryptophan and 5-hydroxyindoleacetic acid levels, and reduce 5-HT expression. Concurrent findings indicated decreased MAOA gene expression in the cortex and striatum, resulting in 5-HT system metabolic abnormalities across the cortex, striatum, and hypothalamus. Notably, reduced expression of the 5-HT type 2 receptor gene in the hypothalamus may contribute to altered cortisol levels. More recently, Nagpal’s team^[36] conducted high-throughput target screening and validation experiments during the 43-day-SpaceX CRS-29 mission on the ISS, specifically aiming to alleviate microgravity-induced neuropathological symptoms. Their findings demonstrated significant upregulation of pro-inflammatory factors (e.g., interleukin-6, tumor necrosis factor-α) and increased expression of neurodegenerative markers like Aβ42, phosphorylated tau (pTau), and TDP-43 in three-dimensional brain organoids (e.g., prefrontal cortex, motor neuron organoids) under microgravity. This inflammatory response, closely linked to nuclear factor-κB (NF-κB) signaling pathway activation, exhibited striking similarities to the pathologies associated with Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). Crucially, a study^[36] successfully identified 2 nano-oligomer molecules, NI112 and NI113, through high-throughput screening. These molecules remarkably downregulated multiple neurodegenerative disease biomarkers in space, significantly alleviating microgravity-induced pathological damage^[36]. This breakthrough provides innovative candidate molecules and research insights that are pivotal for future drug development targeting neurodegenerative diseases.

In short, microgravity offers a unique biological lens for unraveling disease mechanisms that are difficult to model on Earth. By inducing distinct cellular and molecular alterations, it enables more accurate simulation of conditions like muscle atrophy, osteoporosis, and neurodegeneration. These insights not only deepen our understanding of disease progression but also accelerate the identification of novel therapeutic targets. As microgravity-based platforms become more accessible, they are poised to become powerful tools for early-stage drug discovery, offering a new frontier for precision medicine and aerospace medicine.

2.2 Protein crystallization based on microgravity

The microgravity environment in space, by eliminating the effects of convection and sedimentation, serves as an unparalleled “golden laboratory” for protein crystallization^[37-40]. Its unique physical conditions significantly enhance crystal quality, providing critical support for high-resolution structural analysis and structure-based drug design (Figure 3). In recent years, the maturation of experimental platforms aboard the ISS has led to significant advancements in microgravity-assisted protein crystallization research. For example, the “Protein Crystal Growth” (PCG) series of experiments, a collaboration between the National Aeronautics and Space Administration (NASA) and the Japan Aerospace Exploration Agency (JAXA), successfully yielded high-resolution crystals of various human key proteins through static diffusion culture on the ISS. Notably, human interferon regulatory factor-3 (IRF-3), hepatitis C virus core protein, and heat shock protein (HSP90 is a protein closely associated with cancer and metabolic diseases) all produced crystals of superior quality in space compared to ground-based conditions, substantially improving the quality of X-ray diffraction data^[41]. Another compelling example comes from MSD (Merck Sharp & Dohme), which collaborated with the ISSNL to prepare crystalline suspensions of pembrolizumab (Keytruda) during the SpaceX CRS-10 mission. By leveraging the microgravity environment to reduce sedimentation and minimize convective effects, the research team^[10] successfully obtained suspensions with more uniform particle size distribution and enhanced crystallization stability. This experiment provides a crucial demonstration of the direct applicability of microgravity protein crystallization in commercial drug development.

Further validation of this advantage comes from long-term ISS experiments, where the crystal resolution of β-amyloid, a key protein implicated in AD, significantly surpassed that of samples prepared in ground laboratories. This provides a vital molecular foundation for the design of anti-fibrotic drugs^[42]. In summary, microgravity-enabled high-quality protein crystallization presents unique opportunities for pharmaceutical innovation. Improved crystal resolution enhances the structural understanding of existing drug targets, enabling formulation refinement and potential efficacy enhancement of current therapies. More importantly, space-grown protein crystals may reveal novel active conformations or intermediates, accelerating the discovery of first-in-class therapeutics for complex diseases. Crucially, the atomic-level accuracy of these space-derived structures will provide robust training data for AI-driven protein prediction models, significantly strengthening computational drug design pipelines. As space-based crystallization becomes more accessible, it is poised to play a pivotal role in both the refinement of current treatments and the creation of next-generation precision medicines.

2.3 Drug development based on deep space radiation

The deep space radiation environment, characterized by high-energy particles such as protons, alpha particles, and high-energy charged heavy ions (HZE), induces potent biological effects including DNA damage, oxidative stress, and cellular dysfunction^[43]. This unique characteristic offers an unparalleled platform for exploring biological adaptation mechanisms under extreme conditions and for screening damage-resistant molecules. In recent years, this feature has been harnessed as a “natural accelerator” for novel drug development, progressively demonstrating promising applications in areas such as anti-radiation drugs, new antibiotics, and targeted anti-cancer drug screening^[44-47]. For example, NASA is actively collaborating with multiple institutions to establish cell and animal models that utilize simulated deep-space radiation environments. The primary aim is to screen for small-molecule drugs with antioxidant, DNA repair-promoting, or apoptosis-regulating functions to mitigate radiation damage during long-duration spaceflight. Furthermore, a study^[48] of 5 Gram-positive bacteria isolated from the ISS revealed that these microorganisms exhibit convergent adaptive traits in extreme space environments. These traits include mechanosensitive channel proteins regulating osmotic pressure, enhanced DNA repair capabilities, and metabolically associated mobile genetic elements^[48]. This research suggests that these unique genetic characteristics may not only support the production of biomolecules essential for space missions but also highlight their potential pathogenicity and value as novel drug targets. Notably, this extreme radiation environment provides a natural and powerful experimental platform for evaluating countermeasures against nuclear radiation injuries^[49]. Its complex and high-dose exposure conditions closely simulate nuclear accidents or high-risk occupational exposures, thereby offering a realistic model system for preclinical drug evaluation. This makes it highly valuable for the discovery and optimization of innovative radioprotective agents, particularly those aimed at preventing or mitigating acute and chronic radiation syndromes.

In addition to its role in target discovery, the deep space radiation environment plays a pivotal part in evaluating the stability, pharmacokinetics, and shelf-life of drugs under extreme conditions. Space radiation, particularly high-energy ionizing particles, can induce molecular degradation, structural alterations, or changes in bioavailability, posing significant challenges to the long-term storage and efficacy of pharmaceuticals during space missions^[45]. Recent studies^[50-53] have systematically investigated the physicochemical integrity and metabolic profiles of key therapeutic agents(including antibiotics, analgesics, and antiemetics) exposed to the space environment aboard the ISS platforms. These experiments revealed that certain formulations underwent radiation-induced oxidation or hydrolysis, leading to decreased potency or altered pharmacodynamics over time. Such insights are crucial for the design of radiation-hardened drug formulations, encapsulation technologies (e.g., liposomes, nanocarriers), and precision dosing strategies tailored for long-duration missions. Together, these findings provide a scientific foundation for the development of space-compatible pharmaceuticals with optimized stability and therapeutic reliability, ensuring medical readiness for deep space exploration.

As space stations and deep space exploration platforms become more routinely operational, future efforts will strategically focus on systematically leveraging the gene/phenotype mutation effects induced by deep space radiation. By integrating multi-omics analysis (genomics, transcriptomics, proteomics, amd metabolomics), a sophisticated closed-loop system will be established, encompassing “space mutagenesis-phenotype screening-drug target validation”. This advanced approach will facilitate the rapid identification of candidate molecules with superior radiation resistance, stress tolerance, and high activity from extremely adaptive organisms.

2.4 Drug development based on deep space resources

As technologies for deep space exploration and resource development continue to advance, the unique resources found in space are increasingly demonstrating their transformative potential in drug development. Extraterrestrial materials-such as rare earth elements abundant in lunar regolith, the unique mineral compositions and crystal morphologies discovered in meteorites, and organic compounds rich in isomeric carbon from comets offer a wealth of opportunities for pharmaceutical innovation^[54]. These materials not only expand the library of available chemical building blocks but also enable the development of next-generation drug delivery systems.

For instance, lunar soil is known to contain elevated concentrations of rare earth elements such as yttrium, terbium, and lutetium, which are of high value in the biomedical field for applications including precision radiotherapy, contrast agents in advanced imaging, and theranostic nanoplatforms^[17-18]. Meanwhile, the distinctive crystal structures found in certain meteorites may serve as natural templates for the discovery or synthesis of new drug polymorphs with improved solubility, bioavailability, or stability features often critical for the success of small-molecule drugs. Additionally, comet-derived carbon-rich compounds could serve as novel precursors or scaffolds in synthetic medicinal chemistry, offering unusual stereochemistry that is difficult to access via Earth-based resources.

Beyond the chemical composition of these extraterrestrial materials, the space environment itself-characterized by ultra-high vacuum, intense radiation fields, and long-term microgravity creates a unique manufacturing context. These conditions have been shown to enhance the purity, homogeneity, and crystallographic order of pharmaceuticals and carrier systems, enabling the fabrication of high-stability drug crystals, slow-release nanocarriers, and magnetically responsive formulations that are difficult or impossible to reproduce under terrestrial conditions.

In summary, space-derived resources both in terms of raw materials and extreme physical environments present unprecedented opportunities to reimagine the entire pipeline of drug development. From unlocking novel molecular entities to engineering advanced delivery systems, these space-enabled innovations are set to drive a new era of convergence between materials science and pharmaceutical biotechnology, opening promising frontiers for precision and personalized medicine.

3 Challenges and perspectives

The deep integration of space science, materials engineering, and biomedical technology has positioned space pharmaceuticals as a crucial frontier in space medicine and biopharmaceuticals. Leveraging the unique space environment-microgravity, high radiation, vacuum, and minimal convection-enables the creation of high-purity, high-resolution protein crystals, complex molecular configurations, and cellular microstructures unattainable on Earth. However, despite this immense potential, the development of space pharmaceuticals faces significant constraints and challenges (Table 1).

Currently, in-orbit experimental resources are severely limited by concentrated platform availability, scarce opportunities, and constrained, lengthy sample transportation cycles. These factors profoundly impede high-throughput drug screening, systematic pharmacodynamic assessment, and long-term stability testing. Furthermore, the prohibitive cost of in-orbit experiments disproportionately steers current space pharmaceutical research towards high-value-added drugs, such as mRNA vaccines, anti-cancer drugs, and anti-viral agents, leaving conventional medications and chronic disease treatments largely underexplored.

Fortunately, the accelerating commercialization of the space industry is rapidly providing feasible solutions. Firstly, the rise of commercial rockets and small satellite launch services (e.g., SpaceX, Blue Arrow Aerospace) has dramatically reduced orbital transportation costs. Concurrently, the construction of new-generation commercial space stations and experiment platforms (e.g., Axiom Space, Starlab) is democratizing access to affordable and sustainable space experiment opportunities for more research institutions and pharmaceutical companies. Secondly, rapid advancements in miniaturized, modular biological experiment systems and microfluidic chip technology are enabling high-precision, low-volume, and low-energy-consumption operations in space. This significantly boosts experimental output efficiency per unit cost. Additionally, ground-based microgravity simulation platforms, including two-dimensional/three-dimensional rocking incubators, magnetic levitation devices, and critical fluid suspension systems, offer an important complementary solution. These platforms have demonstrated good consistency and reproducibility for studies in cell culture, protein crystallization, and drug delivery. A “ground-space integrated” design strategy-where initial screening and modeling occur on Earth, followed by in-orbit verification and optimization-is thus emerging as a key pathway to enhance the efficiency and cost-effectiveness of space-based pharmaceutical research and development.

Another core challenge for deep space pharmaceuticals is the impact of unstable environmental variables, such as high-energy particle radiation, mechanical vibrations, and fluctuations in temperature and humidity, on drug chemical stability, biological activity, and pharmaceutical properties. Current research indicates that most conventional formulations undergo degradation, aggregation, or component separation during long-term storage in deep space, leading to reduced active ingredient content or the generation of toxic byproducts. A critical obstacle to the industrialization and reliable use of deep space pharmaceuticals is the early stage of research, which manifests as a lack of systematic stability testing and quality control systems for multi-variable space environments.

To address these challenges, several promising approaches are emerging. Environmentally controlled microgravity simulation platforms, such as magnetic levitation, rotating beds, and bioreactor chambers, allow for ground-based experiments that isolate interfering variables. This enables controlled simulations of single factors (e.g., radiation dose, temperature) to clarify their independent effects on drug performance. Concurrently, a long-term quality assurance system for space pharmaceuticals is gradually being established. This includes optimizing sealed packaging materials, selecting high-stability excipients, and developing novel stability evaluation standards specifically tailored for space conditions.

As global aerospace activities intensify and commercial spaceflight and international cooperation rapidly advance, the number of astronauts and their cumulative time in orbit have significantly increased^[55]. Long-duration space missions are transitioning from an “exploration phase” to a “routine residency phase”, imposing heightened demands on personnel health and safety in orbit. However, the existing pharmaceutical system is primarily designed for ground-based clinical indications, lacking systematic research and treatment strategies specifically targeting space-specific disease spectra. This presents a critical challenge for space pharmaceuticals.

Under the complex influence of the space environment, astronauts are susceptible to a range of typical space-related pathological conditions, including immunosuppression, osteoporosis, muscle atrophy, abnormal cerebrospinal fluid distribution, cardiovascular regulatory disorders, insomnia, and emotional disturbances. The physical and psychological impacts of spaceflight are not restricted only to their specific stimuli but can also influence each other, resulting in a complex interplay that can have extensive health consequences for space travelers (Figure 3)^[55]. Critically, medications currently in use are predominantly general-purpose ground-based drugs, whose efficacy and safety have not been systematically validated in the space environment. This leads to issues such as difficulties in dose adjustment, unclear side effects, and significant individual response variations. Therefore, developing targeted drugs and novel formulation systems adapted to the characteristics of the space environment is an indispensable technical support direction for deep space exploration missions.

Looking ahead, space pharmaceuticals are poised for key breakthroughs in several interconnected areas. Firstly, big data analysis integrating astronauts’ multi-omics health data and space physiological characteristics will be crucial. This will help identify molecular targets and pathological pathways of space diseases, driving the evolution of disease diagnosis towards precise identification. Secondly, combining AI-assisted drug screening, structural optimization, and pharmacokinetic modeling technologies can dramatically improve new drug development efficiency and accelerate in-orbit validation processes. Thirdly, with the development of space pharmacies and in-orbit three-dimensional printing pharmaceutical platforms, the ability to prepare personalized, small-dose, and rapid-response drugs will gradually be realized, providing dynamic therapeutic support for long-duration missions. As China’s space station enters routine operations and commercial space payload platforms gradually open, space pharmaceuticals are poised to enter a new phase characterized by high-throughput, scalability, and diversified production. It is imperative to expedite the establishment of standardized systems for space drug research and development, a comprehensive space physiological and pharmacological database, and a robust ground-space collaborative simulation experiment platform. This will facilitate a bidirectional conversion mechanism between “space-based original research” and “ground-based translation”, fully unlocking the potential of space pharmaceuticals to drive advancements in terrestrial medical science and technology, as well as national strategic emerging industries.

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基金资助

the National Natural Science Foundation of China(82272067)

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