Acta Pharmaceutica Sinica B

Targeted intestinal barrier repair via probiotic-derived engineered outer membrane vesicles: A 3A1M strategy with antioxidant, anti-inflammatory, anti-ferroptotic, and microbiome modulation effects

Acta Pharmaceutica Sinica B. 2026, 16(4): 2527-2552.

Intestinal barrier disruption, driven by oxidative stress, ferroptosis, immune imbalance, and gut microbiota dysbiosis, plays a crucial role in inflammatory bowel disease (IBD) pathogenesis. Current treatments are often ineffective and cause side effects, emphasizing the need for novel therapies. Here, we have developed an engineered probiotic-derived outer membrane vesicle (OMV), GDO@CM, combining antioxidant gallic acid (GA) and anti-inflammatory H₂S for targeted intestinal barrier repair. Constructed from Escherichia coli Nissle 1917 (EcN)-derived OMVs, GA and diallyl trisulfide (DATS) are incorporated into the hydrophilic inner cavity and lipid bilayer, respectively, while mannose-decorated chitosan (CM) is electrostatically attached to the OMVs surface, enhancing stability and enabling targeted delivery to damaged colonic lesions. GDO@CM efficiently enters activated immune cells and epithelial cells, where GA scavenges reactive oxygen species and inhibits ferroptosis, while H₂S amplifies anti-inflammatory effects. OMVs further synergize with GA and DATS to suppress pathogenic bacteria. These combined actions facilitate effective barrier repair and alleviate IBD symptoms. Single-cell RNA sequencing reveals that GDO@CM reduces inflammation, increases the proportion of reparative M2 macrophages and intestinal stem cells, and promotes epithelial cell proliferation via the APP/CD74 axis. Our findings establish GDO@CM as a promising multi-target therapeutic for IBD, offering a novel strategy for intestinal barrier restoration.

Recent advances in biomedical applications of lyotropic liquid crystals

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.

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.

Crystal engineering for poorly water-soluble drugs: From design to applications

Acta Pharmaceutica Sinica B. 2026, 16(4): 1848-1882.

The limited aqueous solubility of active pharmaceutical ingredients (APIs) remains a major challenge in drug development, severely compromising clinical performance. Crystal engineering has emerged as a powerful and versatile approach to address this issue by rationally designing API crystal structures through precise control of intermolecular interactions, thereby enhancing solubility, dissolution rates, and ultimately bioavailability. This review systematically summarizes recent advances in crystal engineering strategies for poorly water-soluble drugs, including polymorphs, cocrystals, solvates/hydrates, nanocrystals, organic framework solids, solid solutions, liquid crystals, amorphous solids, and salts. Additionally, key challenges in translational applications are discussed, including structure-property relationship, AI-driven computational modeling, in vitro-in vivo correlation establishment, and advanced crystallization techniques. The review aims to provide strategic insights of crystal engineering for overcoming solubility barriers in next-generation drug formulations.

Deciphering the biological fate of mRNA-LNP-based biologics: A perspective from tissue to intracellular distribution

Xin Xu, Lili Cui, Yong Zhang, Jingkai Gu

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.

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.

Exploring the therapeutic potential of cannabidiol in soft tissue wound healing: Delivery strategies and anti-inflammatory pathways

Acta Pharmaceutica Sinica B. 2026, 16(4): 2174-2195.

This review explores the molecular and cellular pathways of soft tissue wound healing and the potential therapeutic use of the non-psychotropic cannabinoid cannabidiol (CBD), integrating findings from in vitro and in vivo preclinical studies as well as completed and ongoing clinical trials. It provides a comprehensive summary of the next steps in new CBD-based product development by analyzing current trends in dosage optimization, treatment guidance, delivery systems, ranging from liposomes, microemulsions to hydrogels. Additionally, the review examines clinical trials related to CBD formulations, delivery routes, and participant outcomes, offering a deeper understanding of the mechanisms guiding the activity beyond binding to cannabinoid 1 (CB1) and CB2 receptors. Furthermore, it highlights challenges and future perspectives in CBD formulation studies, presenting both currently studied approaches and emerging possibilities for innovation. Therapeutic potential of CBD has proved itself in the recent years and only regulatory issues and clarity in treatment and delivery routes will limit its widespread use in soft tissue healing.

Engineered apoptotic vesicle mimetics with tunable “eat-me” signaling precisely regulate tumor-associated macrophages for potentiating cancer immunotherapy

Acta Pharmaceutica Sinica B. 2026, 16(4): 2498-2512.

Repolarizing immunosuppressive M2-phenotype tumor-associated macrophages (TAMs) and blocking the CD47/SIRPα axis are promising strategies to enhance cancer immunotherapy. However, non-selective disruption of macrophage phenotypic balance and CD47/SIRPα signaling can lead to immune-related side effects. To address this, we develop a smart biomimetic nanoparticle (PARM) loaded with R848 and manganese ions (Mn²⁺). PARM is coated with an apoptotic vesicle membrane and a pH-sensitive PEG corona, enabling targeted delivery to TAMs in the acidic tumor microenvironment (TME). The PEG corona protects the nanoparticle from uptake during circulation and sheds in the TME, exposing the apoptotic vesicle membrane. This triggers specific recognition and uptake by TAMs via the “eat-me” signal. R848 and Mn²⁺ repolarize TAMs into a pro-inflammatory phenotype, while the activation of cGAS-STING pathway by Mn²⁺ reduces SIRPα expression and enhances TAM phagocytosis. In vivo studies demonstrate that PARM remodels the immunosuppressive TME by repolarizing TAMs and promoting CD8⁺ T cell infiltration. This leads to significant inhibition of tumor growth and metastasis. These findings highlight the multifaceted role of the cGAS-STING pathway in TAM modulation and present a novel strategy for enhancing macrophage-based cancer immunotherapy.

Author correction to “The crucial function of IDO1 in pulmonary fibrosis: from the perspective of mitochondrial fusion in lung fibroblasts and targeted molecular inhibition” [Acta Pharmaceutica Sinica B 15 (2025) 3125-3148]

Acta Pharmaceutica Sinica B. 2026, 16(4): 2598-2599.

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.