Xiaoling Gao

Peripheral myeloid cells are key regulators of systemic inflammation and promising targets for immune intervention in Alzheimer’s disease (AD). However, selective in vivo small interfering RNA (siRNA) delivery to these cells remains challenging because conventional lipid nanoparticles often exhibit predominant hepatic accumulation and usually require ligand or antibody modification for immune-cell targeting. Here, we report a structure-engineered lipid–mineral nanoparticle platform, termed MCP, for ligand-free myeloid RNA interference (RNAi) delivery. MCP integrates a calcium phosphate mineral phase with a phosphatidic acid-enriched lipid interface, enabling efficient siRNA incorporation. The Ca2+–lipid cooperative architecture promoted macropinocytosis-dependent uptake and preferential siRNA delivery to peripheral myeloid cells in vivo, particularly Ly6Chigh monocytes and macrophages, with enhanced delivery under AD-associated inflammatory conditions. Systemic delivery of MCP carrying siRNA against triggering receptor expressed on myeloid cells 1 (TREM1) attenuated neuroinflammatory and neurodegenerative pathology in an AD mouse model, supporting peripheral myeloid reprogramming as a route to modulate central nervous system (CNS) disease progression. Notably, MCP also achieved efficient TREM1 silencing in AD patient-derived peripheral blood mononuclear cells (PBMCs) and restored TREM1 expression toward healthy-control levels. This work establishes a structure-driven, ligand-free lipid–mineral RNAi platform for peripheral immune intervention in AD.

Central nervous system (CNS) injury is a leading cause of death and long-term disability worldwide. Neurological deficits reflect disruption of central neural circuits. A major barrier to circuit repair is the intrinsically low regenerative potential of adult CNS neurons—linked in part to failure of injury-induced nuclear export of class IIa histone deacetylases (notably HDAC5)—together with a hostile post-injury microenvironment. Here we present a multifunctional nanosystem, encapsulating the class IIa HDAC4/5-selective inhibitor LMK-235 and featuring an electroactive polyaniline coating with asymmetrically distributed 5-hydroxytryptamine moieties. Upon reaching the lesion, our nanosystem assembles into large-pore scaffolds that (i) inhibit the activity of nuclear-retained class IIa HDACs in neurons and thereby reactivate intrinsic regenerative programs, (ii) regulate microglial activation to mitigate neuroinflammation, and (iii) provide an electroactive interface promoting activity-dependent synaptic reconnection. This multi-pronged approach illustrates an integrated platform with translational potential for CNS disorders in which circuit disconnection constrains recovery.

Precise and efficient delivery of messenger RNA (mRNA) to extrahepatic tissues remains a major challenge in advancing mRNA-based therapeutics. Although enveloped viruses and virus-like particles (VLPs) serve as natural RNA delivery systems with varied extrahepatic targeting capabilities, their clinical translation is often hampered by bottlenecks in tunability, safety, immunogenicity, and scalability. Here, we developed a bottom-up self-assembling enveloped virus-mimicking particle (EVMP) composed of highly simplified yet high-performance virus-mimicking peptide (VMP) and tissue-targeting envelope phospholipids. By employing virtual screening via molecular dynamics simulation, directed evolution via key assembling domain mutation, strategic N-terminal fatty acylation modifications, and precise adjustments to envelope phospholipid composition, we achieved high-efficiency delivery of mRNA to organs such as the lungs and spleen. Notably, the optimized lung-targeted EVMP achieved transfection in 37% of total lung cells, including 73% of endothelial cells and 28% of immune cells. In a metastatic lung tumor model, the lead EVMP loaded with IL-12 mRNA effectively suppressed tumor progression. Notably, EVMP demonstrated excellent long-term biosafety and the capacity for repeated administration, owing to their minimal immunogenic profile. This biomimetic virus-mimicking nanoplatform represents a transformative advance in mRNA delivery technologies, enabling effective and safe mRNA-based therapy for extrahepatic diseases. Furthermore, it establishes a generalizable strategy for bottom-up engineering of biomimetic materials with programmable tissue tropism and modular functionality.

Pathological neovascularization is a major cause of vision loss in various ischemic and inflammatory ocular fundus diseases, with current anti‐VEGF therapies requiring invasive and frequent intravitreal injections. In this study, a Trojan horse‐inspired biomimetic lipoprotein nanocarrier (A‐PA‐αCPP) is developed for noninvasive anti‐VEGF therapy via topical administration. Utilizing phosphatidic acid (PA), specifically 1,2‐dioleoyl‐sn‐glycero‐3‐phosphate (DOPA), as the sole phospholipid, the nanocarrier enables electrostatic tethering of aflibercept, with a cell‐penetrating peptide (CPP)‐functionalized apoA1 mimetic peptide (αCPP) incorporated through self‐assembly. Molecular dynamics simulations and intermolecular interaction experiments confirm effective PA–protein interactions and αCPP incorporation. The nanocarrier demonstrates high encapsulation efficiency, size uniformity, and long‐term stability. It enhances transcellular and paracellular transport by promoting cellular uptake, bypassing lysosomal degradation, and modulating tight junctions. When topically administered, A‐PA‐αCPP efficiently delivers to the posterior segment via corneal and conjunctival–scleral–choroidal pathways. In a laser‐induced choroidal neovascularization (CNV) mouse model, A‐PA‐αCPP eye drops show therapeutic efficacy comparable to a single intravitreal injection, while maintaining excellent ocular and systemic biocompatibility. This biomimetic platform highlights the potential of PA‐mediated protein binding in nanocarrier design, offering a promising strategy for home‐based anti‐VEGF therapy and extending the potential to other protein‐based therapeutics.

Drug‐induced liver injury (DILI), predominantly caused by acetaminophen (APAP) overdose, is characterized by excessive reactive oxygen species (ROS) production and subsequent hepatocyte necrosis. Although N‐acetylcysteine (NAC) remains the only approved treatment, its effectiveness is limited by a narrow therapeutic time window and reduced efficacy in advanced cases. To address these limitations, an innovative therapeutic approach is developed utilizing ceria's antioxidant properties. In this study, a reconstituted high‐density lipoprotein‐encapsulated ceria nanocatalyst (CeO₂‐rHDL) is engineered to overcome the aggregation tendency and targeting limitation of naked ceria nanoparticles. These findings revealed that CeO₂‐rHDL enters hepatocytes through macropinocytosis, a process synergistically enhanced by both APAP and NAC, facilitating efficient liver targeting. The nanocatalyst demonstrated remarkable therapeutic efficacy by restoring mitochondrial function through ROS reduction. When combined with NAC, CeO₂‐rHDL significantly improved survival outcomes in DILI mice. This lipoprotein‐based nanocatalyst system represents a promising therapeutic strategy for DILI treatment, offering enhanced targeting capabilities and improved therapeutic efficacy.

In the ever-evolving biomedical field, the nano-based drug delivery system has emerged as a revolutionary and transformative force. It has shattered the traditional boundaries of drug delivery, thereby unfurling novel and exciting vistas for the development of highly innovative drug delivery modalities. In recent years, brain-targeting nano drug delivery systems have garnered increasing attention from researchers, clinicians, and the scientific community at large. This newfound focus is primarily attributable to the truly remarkable strides made in both the quantity and quality of related research efforts. Characterized by high brain penetration efficiency, elevated bioavailability, and controlled release properties, these systems hold significant promise for the treatment of central nervous system (CNS) disorders. Nevertheless, it is an inescapable reality that the vast majority is still in the preclinical research phase. The entry of nanocarriers to the brain is limited to such critical challenges as the restrictive blood-brain barrier (BBB), nonspecific distribution, and potential nanotoxicity. Addressing these challenges—particularly improving the efficacy and safety of BBB penetration, enhancing targeting specificity, and optimizing brain clearance mechanisms—remains essential for the clinical translation of these technologies. This review discusses the methods for brain-targeted nano drug delivery systems to overcome BBB, including using brain-targeted ligands to modify nanoparticles to interact with BBB for crossing or repairing BBB, using external physical stimuli to open BBB, and avoiding BBB by entering the brain through peripheral pathways. To further enhance the precision and efficacy of treatment, continuous exploration and breakthroughs are being made in research targeting specific lesions and particular cell subpopulations within the brain. By delving into the distribution, differential characteristics of different brain cell types and their roles in promoting specific brain functions and neuropathological processes, nano-based drug delivery systems can be meticulously designed to achieve precise targeted delivery, thus driving the development of multimodal therapy and personalized medicine. The biocompatibility and safety of nano drug delivery systems are crucial criteria for clinical translation. Therefore, this review also explores the intracerebral fate and clearance mechanisms of nano-based drug delivery systems, aiming to optimize future nano-based drug delivery systems in terms of entering into the brain safely and efficiently, with controllable and precise targeting, and can be metabolized and cleared. Ultimately, we perform a systematic analysis of the research status of these representative nano-based drug delivery systems, especially those that have entered the clinical trial stage or are expected to enter clinical applications. We highly value the mechanisms of entering the brain, therapeutic effects and safety of these systems, aiming to provide a framework for designing more efficient, selective, and biocompatible brain-targeting drug delivery systems to advance the treatment of brain diseases. By doing so, it is hoped that this review will contribute significantly to propelling the development of clinical treatments for brain diseases, bringing new hope and improved outcomes for patients suffering from these debilitating conditions.

Neurotropic factors, crucial for neural cell maturation and proliferation, hold great therapeutic potential for treating neurodegenerative diseases but face challenges in brain delivery. This study introduces a novel membrane budding‐inspired lipoprotein biomimetic nanocarrier for efficient packaging and precise brain delivery of brain‐derived neurotrophic factor (BDNF). The nanocarrier is created by mixing protein‐loaded biomimetic gel with liposomes composed of lipids prone to forming liquid‐disordered and liquid‐ordered phases. This interaction triggers phase separation and lipid membrane rearrangement, enabling effective protein encapsulation. To enhance blood‐brain barrier permeability and target damaged cerebral vasculature in Alzheimer's Disease, the nanocarrier (RAP‐BHP‐rHDL) is functionalized with Apolipoprotein E3 and αRAP peptides. The obtained RAP‐BHP‐rHDL alleviates neuronal damage, promotes neurogenesis, normalizes the cerebral microvasculature, improves the function of neurovascular units, and restores memory function in 5 × FAD mice. This innovative packaging approach and biomimetic nanocarrier design offer a promising strategy for delivering neurotropic factors to the central nervous system, potentially advancing the management of neurodegenerative diseases.

Recent years have witnessed rapid progress in the discovery of therapeutic proteins and peptides for the treatment of central nervous system (CNS) diseases. However, their clinical applications have been considerably hindered by challenges such as low biomembrane permeability, poor stability, short circulation time, and the formidable blood-brain barrier (BBB). Recently, substantial improvements have been made in understanding the dynamics of the BBB and developing efficient approaches for delivering proteins and peptides to the CNS, especially by using various nanoparticles. Herein, we present an overview of the up-to-date understanding of the BBB under physiological and pathological conditions, emphasizing their effects on brain drug delivery. We summarize advanced strategies and elucidate the underlying mechanisms for delivering proteins and peptides to the brain. We highlight the developments and applications of nanocarriers in treating CNS diseases via BBB crossing. We also provide critical opinions on the limitations and obstacles of the current strategies and put forward prospects for future research.

Protein therapeutics are anticipated to offer significant treatment options for central nervous system (CNS) diseases. However, the majority of proteins are unable to traverse the blood–brain barrier (BBB) and reach their CNS target sites. Inspired by the natural environment of active proteins, the cell matrix components hyaluronic acid (HA) and protamine (PRTM) are used to self‐assemble with proteins to form a protein‐loaded biomimetic core and then incorporated into ApoE3‐reconstituted high‐density lipoprotein (rHDL) to form a protein‐loaded biomimetic nanocarrier (Protein‐HA‐PRTM‐rHDL). This cell matrix‐inspired biomimetic nanocarrier facilitates the penetration of protein therapeutics across the BBB and enables their access to intracellular target sites. Specifically, CAT‐HA‐PRTM‐rHDL facilitates rapid intracellular delivery and release of catalase (CAT) via macropinocytosis‐activated membrane fusion, resulting in improved spatial learning and memory in traumatic brain injury (TBI) model mice (significantly reduces the latency of TBI mice and doubles the number of crossing platforms), and enhances motor function and prolongs survival in amyotrophic lateral sclerosis (ALS) model mice (extended the median survival of ALS mice by more than 10 days). Collectively, this cell matrix‐inspired nanoplatform enables the efficient CNS delivery of protein therapeutics and provides a novel approach for the treatment of CNS diseases.

Overactivation of cyclic GMP-AMP synthase (cGAS) is implicated in the occurrence of many inflammatory and autoimmune diseases, and inhibition of cGAS with a specific inhibitor has been proposed as a potential therapeutic strategy. However, only a few low-potency cGAS inhibitors have been reported, and few are suitable for clinical investigation. As a continuation of our structural optimization on the reported cGAS inhibitor 6 (G140), we developed a series of spiro[carbazole-3,3'-pyrrolidine] derivatives bearing a unique 2-azaspiro[4.5]decane structural motif, among which compound 30d-S was identified with high cellular effects against cGAS. This compound showed improved plasma exposure, lower clearance, and an oral bioavailability of 35% in rats. Moreover, in the LPS-induced acute lung injury (ALI) mice model, oral administration of compound 30d-S at 30 mg/kg markedly reduced lung inflammation and alleviated histopathological changes. These results confirm that 30d-S is a new efficacious cGAS inhibitor and is worthy of further investigation.