Acta Pharmaceutica Sinica B

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Outer membrane vesicles: Versatile nanocarriers for therapeutic delivery and immune modulation

Jinlong Yang, Tang Wang, Yuekai Zheng, Yuning Wei, Juan Tao, Zhongjian Chen, Jianping Qi

Acta Pharmaceutica Sinica B. 2026, 16(4): 1914-1942.

Outer membrane vesicles (OMVs) are nanoscale lipid-bilayer vesicles naturally released by Gram-negative bacteria. By packaging membrane proteins, lipopolysaccharide-derived pathogen-associated molecular patterns, nucleic acids, and metabolites, OMVs integrate intrinsic bioactivity with cargo capacity and have emerged as a versatile platform for therapeutic delivery and immune modulation. In this review, we summarize current understanding of OMV biogenesis, composition, and physicochemical features that shape biodistribution and immunogenicity. We then discuss engineering strategies ranging from genetic rewiring of parental strains and detoxification of lipid A to surface functionalization, hybrid membrane assembly, and stimuli-responsive formulations that enable controllable targeting, loading, and release. Recent progress is highlighted in anti-tumor therapy, nanovaccines for infectious diseases and cancer, and nucleic acid delivery for gene regulation. Finally, we analyze key barriers to clinical translation, including endotoxin-associated safety, batch-to-batch heterogeneity, scalable manufacturing, and standardization of quality attributes. Addressing these challenges through rational design and robust production pipelines will be essential to advance OMV-based therapeutics toward safe, effective, and manufacturable clinical products.
Deciphering the biological fate of mRNA-LNP-based biologics: A perspective from tissue to intracellular distribution

Acta Pharmaceutica Sinica B. 2026, 16(4): 1943-1970.

The remarkable clinical success of mRNA-lipid nanoparticle (mRNA-LNP) vaccines, particularly evidenced by their pandemic-era impact and subsequent 2023 Nobel Prize recognition, has intensified global efforts to expand their application toward therapeutic biologics. Despite showing strong preventive effects, there are still fundamental knowledge gaps in comprehensively defining the hierarchical biological trajectory of mRNA-LNP formulations, which spans from initial systemic exposure, tissue-specific biodistribution, and intracellular delivery to ultimate protein expression dynamics. These unresolved mechanistic questions pose significant constraints on the rational design of next-generation mRNA-LNP therapeutics, which face increased demands for precision dosing, therapeutic efficacy optimization, and enhanced safety profiles. This review discusses the in vivo fate of mRNA-LNP, focusing specifically on blood/tissue/cellular distribution and kinetics/exposure profiles of both intact mRNA-LNP and dissociated components post-administration. It discusses key factors influencing the distribution of expressed protein and summarizes the corresponding research toolkits along with their advantages and disadvantages. Additionally, it compiles strategies to enhance delivery efficacy, tissue tropism, and safety profiles of mRNA-LNP. We anticipate a better understanding of the biological processes and dynamic pattern of mRNA-LNP, which will accelerate the development of next-generation mRNA biologics with predictable safety and delivery efficiency.
Cuproptosis-based nanomedicine in cancer metastasis synergistic therapy

Kan Zhou, Zi-Zhan Li, Yi Liu, Lei-Ming Cao, Han-Yue Luo, Guang-Rui Wang, Kang-Ning Wang, Jinmei Wu, Bing Liu, Zhiyong Song, Lin-Lin Bu

Acta Pharmaceutica Sinica B. 2026, 16(4): 1971-1990.

Cancer metastasis is a critical indicator of cancer progression and serves as a major cause of cancer-related deaths. Cuproptosis is a novel form of regulated cell death proposed in 2022. Unlike ferroptosis and other known regulated cell deaths (RCDs), cuproptosis has a unique regulatory pathway, and its major biochemical features include copper overload, lipoylated tricarboxylic acid cycle protein aggregation, and the loss of iron-sulfur cluster protein. Cuproptosis-based nanomedicine provides novel therapeutic insights for metastatic cancer treatment. The close link between cuproptosis and cancer therapy has been explored, and several therapeutic strategies have been developed, including copper ionophores and drug delivery systems. Cuproptosis-based nanotherapeutic strategies may enable controlled and selective drug release, and through the multifaceted actions of copper metallocompounds, achieve multimodal theranostic modalities or organically synergize with other regulated RCD pathways. This integration enhances antitumor effects and biosafety, overcomes tumor resistance, and improves the tumor microenvironment. In this review, we systematically delineate the mechanisms of cuproptosis and its current therapeutic implications in metastatic malignancies. We further critically analyze these synergistic therapeutic approaches, prospect emerging applications of cuproptosis-based nanomedicine in metastatic oncology, and highlight their untapped therapeutic potential. Ultimately, we anticipate this exploration will inform innovative clinical management strategies for cancer patients with metastasis.
Fluorescence bioimaging of drug nanocarriers based on Förster resonance energy transfer, aggregation-induced emission and aggregation-caused quenching

Acta Pharmaceutica Sinica B. 2026, 16(4): 1991-2028.

The introduction of environment-responsive probes has greatly improved the accuracy of fluorescence bioimaging in evaluating drug nanocarriers. This review highlights the key roles of Förster resonance energy transfer, aggregation-induced emission, and aggregation-caused quenching in advancing nanomedicine. These technologies have enhanced our understanding of nanocarrier pharmacokinetics, biodistribution, and intracellular behavior, providing valuable insights for optimizing drug delivery systems. Their integration into imaging platforms has enabled precise monitoring of nanocarriers in complex biological environments. This review outlines detailed progress in the use of environment-responsive probes, emphasizing their importance in improving the design and effectiveness of nanomedicines. Looking forward, advances in probe engineering and multimodal imaging, combined with computational tools, are expected to drive the development of more targeted, efficient, and personalized therapeutic strategies.
Advanced oral drug delivery systems: Current challenges and emerging technologies

Satomi Onoue, Kohei Yamada, Hideyuki Sato

Acta Pharmaceutica Sinica B. 2026, 16(4): 2029-2042.

Oral dosage is the most commonly used and preferred method of drug administration due to its several advantages, including non-invasiveness, patient adherence, and ease of use. However, oral bioavailability can be influenced by several factors, such as drug solubility and mucosal permeability in the gastrointestinal tract, sometimes leading to poor and/or inconsistent absorption. In particular, low aqueous solubility presents a significant challenge in achieving adequate oral bioavailability and therapeutic effectiveness for many pharmaceutical compounds. Attempts to overcome these limitations have focused on deeper understanding of the physicochemical, biochemical, and biological barriers that limit overall drug bioavailability. To ensure better and stable pharmacokinetic behavior of orally administered drugs, various formulation strategies have been developed to enhance solubility, dissolution rate, membrane permeability, and overall oral bioavailability. This review article explores recent advancements in formulation techniques aimed at improving the biopharmaceutical properties of orally administered drugs. The challenges and development aspects of oral dosage forms are also addressed.
Recent advances in biomedical applications of lyotropic liquid crystals

Guojin Liu, Yuanmei Yang, Qing Wu, Zhongjian Chen, Nadia M. Hamdy, Amr Amin, Gang Chen, Yi Lu

Acta Pharmaceutica Sinica B. 2026, 16(4): 2043-2067.

Lyotropic liquid crystals (LLCs), formed through the self-assembly of amphiphilic molecules in polar solvents, offer thermodynamic stability and tunable mesophases (lamellar, hexagonal, and cubic), making them a versatile platform for biomedical applications. Their structural adaptability enables enhanced drug stability, improved bioavailability, and controlled release, which are advantageous for various therapeutic strategies. LLC-based systems have shown significant promise in drug delivery, long-acting therapies, anti-infective treatments, and wound healing. Their diverse formulation options, including gels, nanoparticles, and in situ forming precursors, support multiple routes of administration, such as oral, intravenous, dermal, ocular, and intranasal. This review summarizes recent advances in the design and functionalization of LLC systems, with a focus on their ability to overcome physiological barriers, enhance therapeutic efficacy, enable targeted delivery, and support prolonged treatment regimens. Challenges in clinical translation and future research directions are also discussed to facilitate the transition from bench to bedside.
Artificial intelligence for drug delivery: Yesterday, today and tomorrow

Acta Pharmaceutica Sinica B. 2026, 16(4): 2068-2092.

The global pharmaceutical drug delivery market is forecasted to grow to USD 2546.0 billion by 2029. The expanding pharmaceutical market urgently needs a more efficient drug research and development paradigm. Artificial intelligence (AI) is revolutionizing drug delivery by offering alternatives to traditional trial-and-error experimental approaches. This review systematically traces the technological evolution from early simple models to current advanced AI algorithms in various applications, ranging from formulation optimization to the prediction of critical formulation parameters and de novo material design. To enhance the reliability of AI applications in drug delivery, we present comprehensive guidelines and “Rule of Five” (Ro5) principles to systematically direct researchers in utilizing AI in formulation development. This “Ro5” includes the following criteria: a formulation dataset containing at least 500 entries, coverage of a minimum of 10 drugs and all significant excipients, appropriate molecular representations for both drugs and excipients, inclusion of all critical process parameters, and utilization of suitable algorithms and model interpretability. The review concludes with insights into emerging trends and future directions, including the utilization of large language models, multidisciplinary collaboration opportunities, talent development, and culture transformation, aimed at facilitating a paradigm shift toward AI-driven drug formulation development.
Inhaled nucleic acid delivery systems for the treatment of pulmonary interstitial diseases: Challenges and opportunities

Acta Pharmaceutica Sinica B. 2026, 16(4): 2093-2118.

The treatment of interstitial lung diseases (ILDs) was important to reduce the inflammation or fibrosis within the interstitial space. In recent years, a variety of undruggable ILDs targets were emerged for anti-inflammation and anti-fibrosis therapy. The development of RNA delivery system provided the potential for undruggable targets to the lung via inhalation. However, the RNA delivery systems still faced the challenges, including the protection of the stability of RNA platform, increasing the effective delivery to the targeted cells, and selective escaping of RNA molecules into the cytoplasm. In this review, we first summarized the physiological and biological barriers of RNA inhaled platform. Subsequently, the progress of inhaled RNA delivery system and their therapeutic efficiency have been systematically addressed for the application of ILDs. Finally, in the design of an inhaled RNA delivery system, key factors needed to consider and perspectives are discussed.
Novel liquid-based approaches for transmucosal drug delivery

Acta Pharmaceutica Sinica B. 2026, 16(4): 2119-2152.

Advancements in drug discovery, such as artificial intelligence, computational technology, and combinatorial chemistry, have led to numerous new promising drug candidates. However, most still fail to reach the market due to poor physicochemical properties, resulting in off-target or toxic effects. As a potential solution, non-invasive and targeted drug delivery at mucosal surfaces can deliver drugs directly to therapeutic sites to avoid off-target effects, decrease required drug doses, bypass hepatic first-pass metabolism, and circumvent uncontrolled drug release. Liquid-based drug delivery systems have advanced tremendously over recent years, with novel dosage forms such as ionic liquids, liquid crystals, stimuli-responsive phase transforming liquid systems, nanoemulsions, double-emulsions, self-emulsifying delivery systems, and eutectic systems being developed. These systems hold vast promise for transmucosal drug delivery as liquids generally provide superior spreadability compared to solid dosage forms, and some liquid systems provide prolonged mucosal retention times compared to conventional solutions. However, liquid dosage forms present regulatory challenges such as preservation, sterility, and stability requirements. This review discusses novel liquid-based formulation approaches to cross the ocular-, nasal-, oromucosal-, and vaginal mucosal barriers emphasizing advanced liquid drug delivery systems and the progress made toward clinical translation as a platform for future transmucosal liquid-based dosage form development.
Lipid-based nanosystems for atherosclerosis treatment: Evolving approaches and novel therapeutic strategies

Acta Pharmaceutica Sinica B. 2026, 16(4): 2153-2173.

Atherosclerosis, the leading cause of cardiovascular diseases, has become increasingly prevalent worldwide, driving the need for innovative therapeutic strategies to improve clinical outcomes. Lipid-based nanosystems have emerged as promising drug delivery platforms due to their biocompatibility, versatility, and proven clinical track records. Among them, traditional systems such as liposomes have been extensively applied in atherosclerosis therapy, primarily for their well-established safety profile and their capacity to deliver both hydrophilic and hydrophobic agents. However, emerging research has expanded the scope of lipid-based nanosystems to include lipid nanoparticles, lipoprotein-based nanosystems, cell membrane-coated nanosystems, and so on. These systems have demonstrated great promise in addressing the complex and heterogeneous nature of the disease. This review aims to provide a comprehensive overview of lipid-based nanosystems, from traditional formulations to cutting-edge innovations, and their evolving applications in the treatment of atherosclerosis. We also discuss the challenges associated with the clinical translation of these systems, as well as future prospects for developing more effective and personalized therapeutic strategies. In conclusion, lipid-based nanosystems provide a promising option for atherosclerosis treatment, potentially driving the progress of novel therapeutic strategies.

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