没了“标准答案”，小核酸药还能怎么走？

编者按：过去十年，寡核苷酸疗法从早期的科学探索逐步发展为更成熟的治疗方式，从罕见的神经系统疾病到更常见的心血管代谢疾病，寡核苷酸疗法正在不断拓展疾病治疗的边界。同时，化学修饰和递送技术的突破让寡核苷酸的组织递送效率获得显著提升。随着基础科学日益复杂，行业面临的核心挑战已转变为：如何将科学成果转化为可行的治疗方案。在这一过程中，技术、转化、制造与开发能力，正成为应对寡核苷酸开发的重要支撑。

为助力全球合作伙伴推进创新寡核苷酸疗法研发，药明康德建立了跨学科的发现与评价体系。平台整合寡核苷酸序列设计与优化、递送工具发现、体内外功能验证和转化评估等全链条能力，支持合作伙伴优化递送策略，推动从递送分子发现到体内概念验证的高效衔接。

近期，药明康德生物学业务平台（WuXi Biology）执行主任Sajesh Parathath博士在Pharmaceutical Outsourcing杂志发表专题文章，围绕寡核苷酸药物的分子设计优化、肝外递送技术突破、一体化开发策略等行业核心话题展开探讨，为全球寡核苷酸疗法研发提供更多思路。

从“有生物学效应”，到真正“做成药”

寡核苷酸疗法能够在RNA层面直接对疾病进行干预，通过抑制致病蛋白表达、调控RNA剪接、恢复异常的生物学通路等方式，有望从根本上改变疾病的进程。过去十年间寡核苷酸疗法已逐渐发展成为一种成熟的治疗方式。

小干扰RNA（siRNA）和反义寡核苷酸（ASO）是推动寡核苷酸疗法发展的核心工具。剪接转换寡核苷酸（SSO）、小激活RNA（saRNA）、微小RNA调节剂以及RNA适配体等不同机制也不断涌现，治疗范围也从罕见神经系统疾病，逐步延伸至心血管、代谢等更常见的疾病领域。

然而，随着研发深入，研发人员也越来越清楚地认识到在实验室中观察到有潜力的生物学效应仅是药物研发的起点。随着技术持续演进，真正的难题正从“能不能起作用”，逐步转变为“能否开发成一款真正的药物”。

第一关：先让寡核苷酸更像一款“药”

寡核苷酸疗法走向成熟依赖于解决两个挑战：一是提升寡核苷酸分子药物特性使其具备足够的稳定性；二是精准递送至靶组织和靶细胞。

RNA和DNA分子本身的药物属性并不理想。未经化学修饰的siRNA和ASO极易被核酸酶降解，其分子量较大、带有大量负电荷，难以高效穿过细胞膜。尤其是siRNA，如何从内体中有效释放、抵达细胞质并发挥作用仍是影响递送效率的关键限速步骤之一。当靶组织位于肝外时，这一问题往往更加突出。

为改善寡核苷酸的药物特性，化学修饰已经成为现代寡核苷酸药物设计中不可或缺的核心环节。以siRNA为例，常见策略包括2′-O-甲基（2′-OMe）和2′-脱氧-2′-氟（2′-F）核糖修饰、硫代磷酸酯（PS）骨架修饰，以及5′-（E）-乙烯基膦酸酯（5′-（E）-VP）等结构修饰。2′-OMe和2′-F修饰在兼容RNA诱导沉默复合物（RISC）装载的同时，能有效提高分子的稳定性和活性并减少免疫激活；5′-（E）-VP的存在则提高了siRNA的稳定性和效力；在双链siRNA末端引入PS修饰有助于保护免受核酸外切酶降解。

ASO的设计同样经历了多轮迭代。未经修饰的ASO稳定性较差，组织和细胞摄取也较为有限。第一代ASO通过引入PS骨架修饰有效提高了分子亲脂性，支持与血清蛋白结合，并有效减少经肾脏的快速清除。第二代ASO则进一步引入2′-O-甲氧基乙基等核糖修饰，以增强对靶RNA的亲和力、提高抗核酸酶降解能力，同时改善组织半衰期和非特异性相互作用。此外，磷酰二胺吗啉代寡核苷酸（PMO）和硫代吗啉代寡核苷酸（TMO）等特殊骨架修饰策略可增强稳定性并降低免疫原性，延长半衰期，并广泛用于外显子跳跃疗法，这一机制在杜氏肌营养不良症（DMD）中尤为重要。

图片来源：123RF

如果说化学修饰决定了“分子能否在体内存活”，那么更加棘手的问题，就是“它能否精准到达正确的位置”。

第二关：从肝脏走向肝外，递送难度陡增

肝脏是寡核苷酸药物最早取得重要临床突破的靶器官之一。脂质纳米颗粒（LNPs）和三价N-乙酰半乳糖胺（GalNAc）偶联技术发挥了关键作用：首个获批的siRNA药物正是依赖LNP实现系统递送；此后，多款siRNA药物借助GalNAc偶联技术，成功实现了对肝细胞的高效靶向递送。

肝脏靶向递送的成功拓展了进一步思考：能否将这种递送能力复制到肝脏以外的组织？

对于LNP而言，实现肝外递送的首要挑战是减少其天然的肝脏富集倾向，同时增强颗粒向目标组织定向分布。为此，研究人员正在探索多种策略，包括调整颗粒大小、表面电荷、脂质组成、给药途径和表面配体，并尝试采用选择性器官靶向等新型技术手段。

抗体、多肽、脂质：肝外递送并无 “标准答案”

在肝外寡核苷酸药物的开发中，基于偶联物的递送策略正成为一个重要的研究方向。

抗体寡核苷酸偶联物（AOCs）将单克隆抗体的靶向特异性与siRNA或ASO的序列特异性相结合，这种方法对于难以通过传统全身给药触及的组织尤为有效。然而，AOC设计仍需优化包括抗体构型、连接子结构、偶联化学方式、寡核苷酸与抗体的摩尔比、受体亲和力以及药代动力学特性在内的多个关键参数以获得理想的治疗效果。

在神经肌肉疾病治疗领域，多肽偶联寡核苷酸（POC）策略可用于改善PMO在DMD外显子跳跃治疗中的核内递送效率。此外，还可利用抗体片段、可切割连接子和寡核苷酸载荷，将具有外显子跳跃功能的寡核苷酸定向递送至骨骼肌和心肌组织。

脂质偶联寡核苷酸（LOC）策略则代表了另一种递送思路。研发人员通过将siRNA或ASOs与不同疏水性的脂质分子连接，调控其血清蛋白结合能力、组织分布特性、肾脏清除速率以及细胞摄取效率。研究表明，在全身给药后，与胆固醇等疏水性较强的脂质偶联的siRNA倾向于优先富集于肝脏；相比之下，与二十二碳六烯酸（DHA）等相对低疏水性的脂质偶联的siRNA更倾向于在肾脏中积累。

这些研究共同说明，肝外递送并不存在一个可以适用于所有项目的“标准答案”。抗体构型、多肽序列、脂质类型、连接子化学、寡核苷酸载荷以及给药策略等因素，共同决定了最终的药理学表现。研发人员所面临的挑战不只是“能否实现递送”，更是针对特定疾病、特定组织和特定靶点，判断哪一种递送方式最为合适。对于当前的寡核苷酸药物研发，很多情况下都需要“具体问题具体分析”。

化学与生物学的融合正在重新定义药物开发

过去几十年，药物开发通常遵循相对清晰的专业分工：化学团队负责分子优化，生物学团队负责功能评估，生产团队负责工艺和规模放大，各团队在较明确的职责边界内独立开展工作。如今，随着药物模式的日益复杂，在药物发现阶段，研发人员就需要将序列设计、分子优化、递送策略和功能验证更紧密地整合，以便尽早判断一个候选分子是否真正具备继续开发的潜力并为后续决策提供可靠依据。

此外，当候选药物推进临床时，化学修饰核苷酸等原料无法稳定采购也可能在后续开发中形成新的瓶颈。同样，在早期生物模型中表现良好的递送技术，可能在放大、表征、放行测试或毒理学方面带来新的挑战。这些问题难以单独解决，因为每一个决策都可能影响下一阶段的发展。尤其对于寡核苷酸药物这类复杂药物，尽早让不同领域的专家围绕同一个项目协同工作尤为重要。如果能在项目早期预见更长远的开发路径，就更有可能提前识别潜在风险，并提升项目推进的效率。这正是一体化开发模式能够真正发挥价值的关键所在。

对于那些拥有独特生物学洞见或前沿技术的平台型生物技术公司而言，这种合作尤其重要。企业可以将有限资源集中在自己最擅长、最具差异化的科学创新上，同时借助外部机构在开发、生产和转化方面的经验，将科学概念逐步推进为真正可开发的候选药物。而合作伙伴可以将从多个项目中积累的经验应用到早期分子选择、递送方案设计以及开发规划，帮助开发者在挑战出现前就预见并提供重要参考。

展望未来：从治疗疾病，到更早地干预疾病

寡核苷酸疗法的发展历程表明，一项真正具有变革性的医学创新，既依赖于基础科学的突破，也需要与之相匹配的基础设施。在未来十年里，随着递送技术和药物属性持续改善，寡核苷酸药物不仅有望用于治疗疾病，还可能逐步拓展至针对疾病的早期干预。

肝外递送技术的持续突破，也有望使药物进入中枢神经系统、骨骼肌、心肌，以及其他过去难以触及的组织。基于这些进展，部分寡核苷酸药物已可实现每年仅需给药一至两次，从而减少频繁治疗给患者带来的负担，并改善长期依从性。随着分子设计的不断演进，研究人员也开始探索利用单个分子同时调节多个靶点，为复杂、多因素疾病提供新的治疗思路。

但真正决定一项科学创新能否走得更远的，是将分子设计、递送策略、生物学验证、转化研究、可规模化生产和后续开发真正系统性地连接起来。因为从“有效果”，到“送得到”，再到“起作用”，直至最终“做成药”，中间仍有漫长的路径需要跨越。唯有建立将这些科学突破持续转化为药物的能力，才能使科学上的可能性最终成为真正惠及患者的治疗选择。

Rethinking the Oligonucleotide Journey

Why integration matters

Over the past decade, oligonucleotide therapies have progressed from early scientific exploration into a more established therapeutic modality. Their central appeal lies in their unique ability to intervene at the transcript level, allowing them either to repress disease-causing proteins or to engineer outcomes that restore pathways that improve the disease state. While small interfering RNA (siRNA) and antisense oligonucleotides (ASOs) remain the foundational vehicles driving this field, the modern toolkit includes additional mechanisms and approaches such as splice-switching oligonucleotides (SSOs), small activating RNAs (saRNAs), microRNA modulators, and RNA aptamers. The therapeutic reach of these modalities can span a broad spectrum of diseases, from rare neurological disorders to more common conditions such as cardiometabolic diseases.

Although advances in chemistry and delivery technologies fuel much of this clinical progress, generating promising laboratory biology is only the initial step.As the underlying science becomes more sophisticated, the greater challenge often lies in assembling the technical, translational, manufacturing, and development capabilities required to convert that science into a viable therapeutic program.Consequently, integrated strategic partnerships play an increasingly critical role for companies navigating the steep execution risks of the oligonucleotide landscape.

The Evolution of Oligonucleotides: Improving Drug-Like Properties and Targeted Delivery

The maturation of oligonucleotide therapies has depended on solving two fundamental challenges:improving their drug-like properties, including metabolic stability, and delivering them to the right tissues and cells.

RNA and DNA-like molecules are not naturally optimized to behave as drugs. Unmodified siRNAs and ASOs are susceptible to nuclease degradation. They are large, highly charged, and often unable to cross cell membranes efficiently. For siRNA in particular, endosomal escape remains one of the most important rate-limiting steps, especially when delivery moves beyond the liver.

To improve the drug-like properties of oligonucleotides, chemistry has become inseparable from the biology of oligonucleotide medicines. For siRNAs, chemical stabilization has evolved from minimal modification to extensive modification. Common strategies include 2’-O-methyl (2’-OMe) and 2’-deoxy-2’-fluoro (2’-F) ribose modifications, phosphorothioate (PS) backbone modifications, and 5’-(E)-vinyl phosphonate (5’-(E)-VP) designs. The 2’-OMe and 2’-F modifications can increase potency and reduce immune activation without interfering with RNA-induced silencing complex (RISC) loading, while the presence of 5’-(E)-VP improve siRNA stability and potency, and PS modifications at the ends of duplex siRNAs help protect against exonucleases.

Image Source: 123RF

The design of ASOs has also progressed through multiple generations. Naturally occurring ASOs are labile and have lower tissue and cellular uptake, which led to the use of PS backbone modification in first-generation ASOs. This modification increases lipophilicity, supports binding to serum proteins, and helps reduce rapid kidney clearance. Second-generation ASOs added 2’-O-methoxyethyl modifications to the ribose in combination with the PS backbone. This chemistry rigidifies the overall structure, increases affinity for target RNA, hinders nuclease attack, decreases nonspecific interactions, and can extend tissue half-life. Other designs, including phosphorodiamidate morpholino oligonucleotides (PMOs) and thiomorpholino oligonucleotides (TMOs), can function as steric blockers for exon skipping, an approach that is especially relevant in Duchenne muscular dystrophy (DMD).

The second major challenge for developing oligonucleotide therapeutics was targeted delivery. The liver provided the first major clinical proving ground for oligonucleotide delivery. Two delivery systems have been especially important: lipid nanoparticles (LNPs) and trivalent N-acetylgalactosamine, or GalNAc, conjugation. The first approved siRNA medicine used LNPs, while most subsequently approved siRNA drugs have used GalNAc conjugation for hepatocyte delivery.

Liver-targeted delivery provided important commercial and clinical proof-of-concept. However,the next frontier is expanding the reach of oligonucleotides to extrahepatic tissues.To extend LNP delivery beyond the liver, researchers are exploring strategies to reduce hepatic uptake of LNPs and retarget them to selected tissues. These strategies include changes in particle size, surface charge, lipid composition, administration route, surface ligands, and selective organ targeting approaches.

Conjugation-based delivery is becoming one of the most important strategies for extrahepatic oligonucleotide therapeutics. Antibody–oligonucleotide conjugates (AOCs) combine the targeting specificity of monoclonal antibodies with the sequence-specific activity of siRNAs or ASOs. This approach is particularly valuable for organs that are difficult to reach through conventional systemic delivery. For central nervous system delivery, transferrin receptor 1 has emerged as an important target because it is abundantly expressed on brain endothelial cells and can support transport across the blood–brain barrier. However,AOC design requires careful optimization of antibody format, linker, conjugation chemistry, oligonucleotide-to-antibody ratio/DAR, receptor affinity, and pharmacokinetic properties to achieve a favorable therapeutic index.

In parallel, the neuromuscular field further illustrates how different delivery architectures can be adapted to the same biological objective. Enhanced delivery oligonucleotide peptide platforms are being used to improve nuclear delivery of PMOs for exon skipping in DMD. Peptide–PMO conjugates have shown improved exon skipping and dystrophin production in DMD models. Other platforms use antibody fragments, cleavable linkers, and oligonucleotide cargos to direct exon-skipping therapeutics toward skeletal and cardiac muscle.

Lipids offer another route to extrahepatic delivery.By conjugating siRNAs or ASOs to lipids with different levels of hydrophobicity, researchers can influence serum protein binding, tissue distribution, renal clearance, and cellular uptake.Studies have shown that, after systemic administration, siRNAs conjugated to more hydrophobic lipids, such as cholesterol, tend to distribute preferentially to the liver. By contrast, siRNAs conjugated to less hydrophobic lipids, such as docosahexaenoic acid (DHA), show a greater tendency to accumulate in the kidney.

Together,these examples show that extrahepatic delivery is not defined by a single technology. Rather, it represents a complex design space in which antibody format, peptide sequence, lipid type, linker chemistry, cargo selection, and dosing strategy all influence the final pharmacological outcome.

While systemic delivery represents a major route for the development of oligonucleotide therapeutics, local delivery remains important. Intrathecal and intracerebroventricular routes can deliver ASOs to the central nervous system. Intravitreal administration can be used for ocular indications. Inhalation may support pulmonary delivery. These routes avoid some systemic barriers, but they also introduce their own constraints, including distribution within the target organ, durability, tolerability, and patient convenience. The future of extrahepatic delivery will likely involve both systemic and local approaches, selected according to disease biology, target tissue, therapeutic window, and desired duration of action.

The central nervous system, muscle, eye, lungs, and immune system are emerging as key frontiers for the next wave of oligonucleotide delivery. Progress in these areas will require more than making oligonucleotides more stable or attaching them to new ligands. It will require matching molecular design with tissue biology. Developers must determine which oligo tool is better suited to a target based partly on where the relevant RNA is located. ASOs may be advantageous for nuclear targets and splice modulation, while siRNAs may offer durable cytoplasmic mRNA silencing. Delivery vehicles must be evaluated not only for target binding, but also for receptor availability, trafficking, endosomal escape, pharmacokinetics, biodistribution, and toxicology.

As these technologies grow in complexity, they are also eliminating the traditional boundaries between scientific disciplines. In parallel, they are broadening the range of addressable diseases toward more prevalent conditions, including those with complex and multifactorial disease biology. Maximizing their potential now requires highly integrated development frameworks that harmonize chemistry, structural biology, translational modeling, and development strategy from the beginning.

The Convergence of Chemistry and Biology Is Redefining Drug Development

For decades, drug development was often organized into relatively distinct disciplines. Chemists optimized molecules. Biologists evaluated function. Manufacturing teams scaled production. Each group operated within well-defined boundaries. Today, that model is rapidly changing.

As modern modalities become more sophisticated, development teams must navigate increasingly complex steps, technologies, and chemistries. During the discovery phase, for example, researchers need integrated capabilities that span from sequence design through functional validation. These capabilities are critical to improving development efficiency and increasing the likelihood of success. Teams also need access to high-fidelity translational models that can generate the high-quality data required for informed decision-making.

Beyond discovery, developers face growing complexity in manufacturing and analytics as these novel modalities advance through development. For example, sourcing chemically modified nucleotides and unnatural amino acids for peptide-conjugated oligonucleotides can become a bottleneck when advancing a preclinical candidate into the clinic. Moreover, unlike traditional small molecules, oligonucleotides—particularly GalNAc-conjugated siRNAs—undergo complex nuclease-mediated metabolism that can vary significantly across biological compartments. These differences may also result in distinct toxicology profiles, making conventional in vitro systems insufficient for translational prediction.

As a result, the traditional boundaries separating disciplines are becoming increasingly blurred.

This is why integrated development is becoming increasingly important for complex modalities. A change that improves potency or tissue uptake may also affect chemistry, manufacturing, and controls (CMC) complexity. Similarly, a delivery technology that performs well in an early biological model may create new challenges in scale-up, characterization, release testing, or toxicology interpretation. These issues are difficult to solve in isolation because each decision can affect the next stage of development.

From discovery to toxicology and development, and from biology to chemistry and strategy, no single individual can possess expertise across the entire process. To reduce friction during handoffs, it is increasingly valuable to bring experts together from the outset to design the best possible development plan, rather than switching teams at each stage. In complex drug development, including oligonucleotide programs, teams that can evaluate therapeutic candidates through both scientific and operational lenses are increasingly needed.

By bringing these capabilities together early, developers can look beyond the immediate next milestone and anticipate challenges three or four stages ahead. That is the true value of an integrated model—and what can make a meaningful difference in the success of drug development.

A Strategic Advantage for Biotech Companies

This trend extends well beyond oligonucleotides. From nanoparticles and antibody-drug conjugates (ADCs) to degraders and other emerging modalities, each technology brings its own manufacturing, analytical, and development complexities. Success now requires teams with experience across a broad range of platforms, as well as the adaptability to navigate modalities that may not yet exist today.

For resource-constrained biotech companies, building this breadth of expertise internally is often not realistic. When funding cycles are longer and budgets are tighter, companies are often forced to make difficult choices. Many organizations enter development with multiple promising assets, only to narrow their focus to a single lead candidate as resources become strained.

As a result, many innovators are seeking partners with integrated development capabilities. They want partners who understand the broader context of the program, proactively solve problems, evaluate alternative paths, and help guide key decisions along the way.

For emerging biotech companies with unique biological insights or technical innovations, this type of partnership can be especially valuable. It allows innovators to remain focused on their core scientific strengths while leveraging external expertise in development, manufacturing, and regulatory strategy.These partners can apply lessons learned across multiple programs to guide molecule selection, delivery strategies, and development planning from the outset, helping developers anticipate challenges long before they emerge.

Looking Ahead

The history of oligonucleotide therapeutics illustrates that transformative medical progress occurs when foundational scientific breakthroughs are matched by equally robust advances in development infrastructure. Over the next decade, oligonucleotides are poised to expand their clinical footprint beyond reactive treatment and toward proactive preventive intervention for highly prevalent chronic conditions.

Continued progress in extrahepatic delivery will unlock reliable, targeted access to the central nervous system, skeletal and cardiac muscle, and other historically restricted tissues. In some cases, these advanced platforms can virtually eliminate traditional patient compliance barriers by only needing one to two administrations of the drug per year. Furthermore, oligonucleotides may be able to engage multiple targets with a single molecule/dose, potentially enabling the treatment of multiple diseases through an integrated therapeutic approach.

Realizing this paradigm shift requires more than designing better molecules. It demands the architecture of highly integrated systems, a framework that seamlessly connects early-stage discovery, translational biology, scalable manufacturing, and commercial execution.Ultimately, the next frontier of medicine will not be defined by isolated laboratory breakthroughs, but by our collective ability to achieve full operational integration, turning scientific possibility into scalable, sustainable patient impact.

参考资料：

[1] Rethinking the Oligonucleotide Journey. Retrieved October 14, 2026 from https://www.pharmoutsourcing.com/Featured-Articles/628188-Rethinking-the-Oligonucleotide-Journey/

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