Precise Delivery Research Articles

Optimizing mRNA delivery: A microfluidic exploration of DOTMA vs. DOTAP lipid nanoparticles for GFP expression on human PBMCs and THP-1 cell line.

This study highlights lipid nanoparticle (LNP) formulations incorporating DOTMA or DOTAP as cationic lipids for the delivery of mRNA encoding Enhanced Green Fluorescent Protein (eGFP-mRNA). The performance of these tailored formulations was benchmarked against a commercial formulation (LipidFlex®, Precigenome), which can also be combined with DOTMA or DOTAP but contains helper lipids of undisclosed composition. LNPs were synthesized using a microfluidic device equipped with a passive Y-shaped microchip, operating at an optimized total flow rate of 6 mL/min and a flow rate ratio of 1:3, with a total lipid concentration ranging from 0.7 to 30 mM. This method produced Single Unilamellar Vesicles (SUVs) with an average size of 150 ± 53 nm and a surface charge of 18 mV. The nitrogen-to-phosphate (N/P) ratio was varied between 250 and 6, modulating the surface charge (from 48 to 18 mV) and the mRNA-eGFP encapsulation efficiency (from 80 % to 70 %, respectively). Cytotoxicity assays and IC50 evaluations on a Hamster Ovarian cell line confirmed that the c-DOTMA formulation achieved an optimal balance of low toxicity and high transfection efficiency. In THP-1 cells, c-DOTMA delivered the highest eGFP expression, reaching up to 25 % transfection efficiency, extremely higher if compared to those observed in the total PBMC population under similar conditions. This selective behavior highlights its potential for precise mRNA delivery to specific immune cell subsets, though further research is required to assess in vivo performance, biodistribution, and immunogenicity.

AgNP-Containing Niosomes Functionalized with Fucoidan Potentiated the Intracellular Killing of Mycobacterium abscessus in Macrophages

Intracellular pathogens represent a challenge for therapy because the antibiotics used need to diffuse into the cytoplasm to target the pathogens. The situation is more complicated in the mycobacteria family because members of this family infect and multiply within macrophages, the cells responsible for clearing microorganisms in the body. In addition, mycobacteria members are enclosed inside pathogen-containing vesicles or phagosomes. The treatments of these pathogens are aggravated when these pathogens acquire resistance to antibiotic molecules. As a result, new antimicrobial alternatives are needed. Niosomes are vesicles composed of cholesterol and nonionic surfactants that can be used for antibiotic encapsulation and delivery. The current study developed a systematic formulation of niosomes to determine the best option for niosome functionalizing for precise delivery to the intracellular pathogen Mycobacterium abscessus. Silver nanoparticles (AgNPs) were synthesized using gallic acid as an antibacterial agent. Then, niosomes were prepared and characterized, following the encapsulation of AgNPs functionalized with a single-chain antibody screened against the cell wall glycopeptidolipid of Mycobacterium abscessus. For a precise delivery of the cargo into macrophages, the niosomes were also functionalized with the polysaccharide fucoidan, taken specifically by the scavenger receptor class A expressed on the surface of macrophages. Results of the study showed a steady decrease in the intracellular pathogen load after 48 h post-infection. In conclusion, this system could be developed into a platform to target other types of intracellular pathogens and as an option for antimicrobial therapy.

Microwave-Responsive Engineered Platelet Microneedle Patch for Deep Tumor Penetration and Precision Therapy.

Controllable and precise delivery of therapeutic agents is critical for effective tumor therapy. However, tumor targeting and the deep penetration of drugs remain among the most challenging issues in achieving controlled delivery. Herein, a novel engineered platelet microneedle patch with a microwave-responsive magnetic biometal-organic framework is proposed to facilitate the combination of the engineered platelet and microwave hyperthermia, enhancing deep drug penetration into tumors and enabling precision therapy. The prepared magnetic biometal-organic framework as nanomedicine exhibits excellent microwave thermal effects. The engineered platelets could be activated in the tumor microenvironment to release PMPs and nanomedicines combined with microwave hyperthermia for enhancing both cell uptake and deep drug penetration into tumors. The developed separable microneedle patch system allows the microneedle tip to be quickly detached from the backing layer and retained within the target tissue for repeated local cancer hyperthermia treatments. By integration of engineered platelets into the microneedle patch, the transdermal deep delivery of drugs could be effectively enhanced for local microwave thermochemotherapy of tumors. This work represents the first attempt to graft microwave-responsive inorganic nanomedicines onto platelets as cell drugs, offering a novel strategy for precise drug delivery activated by microwave thermal therapy.

Macrophage Membrane-Camouflaged Nanozymes for Combating the Oxidative Stress-Microvascular Perfusion Negative Feedback in Ischemia-Reperfusion Induced Acute Kidney Injury.

Oxidative stress plays a critical role in the pathogenesis of ischemia-reperfusion injury (IRI)-induced acute kidney injury (AKI), driving necrosis of proximal tubule cells, inflammation, and capillary rarefaction. Inadequate perfusion resulting from capillary rarefaction can, in turn, induce chronic tissue hypoxia and exacerbate ischemic acute tubular necrosis, leading to an "oxidative stress-microvascular perfusion" negative feedback that further aggravate kidney damage. In this study, a macrophage membrane-camouflaged manganese-based antioxidant nanozyme (MB@LM) is developed for targeted delivery and oxidative stress relief in AKI therapy. By inheriting macrophage surface proteins, MB@LM selectively targets damaged renal tissues that overexpress adhesion molecules like intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), facilitating enhanced accumulation at the injury site. The manganese-based nanozyme core provides antioxidant enzyme-mimicking activities, effectively reducing oxidative stress and inhibiting apoptosis. In IRI-induced AKI mouse model, MB@LM treatment significantly reduces renal damage, restores renal microvascular perfusion as assessed by ultrasound imaging, and alleviated inflammation, demonstrating remarkable therapeutic efficacy. Overall, MB@LM represents a promising targeted therapy for AKI, offering precise delivery, potent antioxidant protection, and anti-inflammatory effects to support renal recovery and improve outcomes for AKI.

Bacterial Systems as a Precision Delivery Platform of Therapeutic Peptides for Cancer Therapy

Bacterial Systems as a Precision Delivery Platform of Therapeutic Peptides for Cancer Therapy

Responsive nanomaterials in biomedicine, patent path and prospect analysis

In recent years, responsive nanomaterials have demonstrated tremendous potential in biomedical applications due to their unique advantages in precise drug delivery and controlled release. For complex diseases such as cancer, chronic inflammation, and genetic disorders, traditional treatment methods are often limited by insufficient targeting and significant side effects. Responsive nanotechnology, by sensing specific internal or external stimuli, has significantly enhanced the precision and efficiency of treatments. This study systematically summarizes the technological trajectory and emerging research directions of responsive nanomaterials through global patent and literature data, employing main path analysis, derivative path analysis, and keyword co-occurrence analysis. The results reveal the evolution of this field, from the optimization of early single-stimulus-responsive nano delivery systems to the rise of theranostics integration, followed by advancements in multi-stimuli-responsive synergistic therapies, and finally, the innovation in biomimetic material design. Each developmental phase has increasingly focused on adapting to complex biological environments, achieving superior targeting performance, and enhancing therapeutic efficacy. Keyword co-occurrence analysis highlights key research hotspots, including biomimetic design, multimodal synergistic therapies, and emerging response mechanisms. In the future, responsive nanomaterials are expected to play a pivotal role in personalized medicine, multifunctional carrier design, and complex disease management, providing novel insights and technological support for precision medicine.

Interval Analysis-Based Optimization: A Robust Model for Intensity-Modulated Radiotherapy (IMRT)

Background: Cancer remains one of the leading causes of mortality worldwide, with radiotherapy playing a crucial role in its treatment. Intensity-modulated radiotherapy (IMRT) enables precise dose delivery to tumors while sparing healthy tissues. However, geometric uncertainties such as patient positioning errors and anatomical deformations can compromise treatment accuracy. Traditional methods use safety margins, which may lead to excessive irradiation of healthy organs or insufficient tumor coverage. Robust optimization techniques, such as minimax approaches, attempt to address these uncertainties but can result in overly conservative treatment plans. This study introduces an interval analysis-based optimization model for IMRT, offering a more flexible approach to uncertainty management. Methods: The proposed model represents geometric uncertainties using interval dose influence matrices and incorporates Bertoluzza’s metric to balance tumor coverage and organ-at-risk (OAR) protection. The θ parameter allows controlled robustness modulation. The model was implemented in matRad, an open-source treatment planning system, and evaluated on five prostate cancer cases. Results were compared against traditional Planning Target Volume (PTV) and minimax robust optimization approaches. Results: The interval-based model improved tumor coverage by 5.8% while reducing bladder dose by 4.2% compared to PTV. In contrast, minimax robust optimization improved tumor coverage by 25.8% but increased bladder dose by 23.2%. The interval-based approach provided a better balance between tumor coverage and OAR protection, demonstrating its potential to enhance treatment effectiveness without excessive conservatism. Conclusions: This study presents a novel framework for IMRT planning that improves uncertainty management through interval analysis. By allowing adjustable robustness modulation, the proposed model enables more personalized and clinically adaptable treatment plans. These findings highlight the potential of interval analysis as a powerful tool for optimizing radiotherapy outcomes, balancing treatment efficacy and patient safety.

Breaking barriers: Smart vaccine platforms for cancer immunomodulation.

Despite significant advancements in cancer treatment, current therapies often fail to completely eradicate malignant cells. This shortfall underscores the urgent need to explore alternative approaches such as cancer vaccines. Leveraging the immune system's natural ability to target and kill cancer cells holds great therapeutic potential. However, the development of cancer vaccines is hindered by several challenges, including low stability, inadequate immune response activation, and the immunosuppressive tumor microenvironment, which limit their efficacy. Recent progress in various fields, such as click chemistry, nanotechnology, exosome engineering, and neoantigen design, offer innovative solutions to these challenges. These achievements have led to the emergence of smart vaccine platforms (SVPs), which integrate protective carriers for messenger ribonucleic acid (mRNA) with functionalization strategies to optimize targeted delivery. Click chemistry further enhances SVP performance by improving the encapsulation of mRNA antigens and facilitating their precise delivery to target cells. This review highlights the latest developments in SVP technologies for cancer therapy, exploring both their opportunities and challenges in advancing these transformative approaches.

Study of the Response and Calibration Procedures of LiF:Mg, Ti TLD-100 for the Dosimetry of Photon Beam

To guarantee quality assurance and quality control of the received radiation dose and treatment level, Thermoluminescent Dosimeter (TLD) is frequently employed in personal control and monitoring equipment. TLDs are commonly used to ensure the precise delivery of radiation doses to patients in clinical radiotherapy, diagnostic radiology, personal radiation monitoring, and environmental radiation dosimetry. Even though the manufacturer made all the TLDs in the same batch, their sensitivity varies. This study aims to examine the TLD crystal calibration process, in particular, the crystal sensitivity and linearity of individual TLDs following exposure to radiation at various dosage levels for precise dosimetric radiotherapy purposes. Herein, a batch of twenty (20) LiF:Mg,Ti dosimeters was used for calibration in the air for low dose levels and in tissue equivalent water phantom for high dose. In this method, dosimetry of 20 sets of TLDs was carried out in the air on the skin of Alderson rando phantom and was exposed by 137Cs source to 1 mSv, 2 mSv, 3 mSv, 4 mSv, 5 mSv, 10 mSv, and 20 mSv dose. Again, TLDs were irradiated to 60Co beams following the reference dosimetry for 50 cGy, 100 cGy, 150 cGy, and 200 cGy at reference depth (5 cm) of a water phantom. The uncertainty of the variation of crystal sensitivity of our TLDs is 0.21%. The dose – response linearity of TLDs in both cases showed to be very close to unity having uncertainty within the recommended limit. This finding supports the clinical practice of measuring precise dosages of radiation using TLDs and essential to guarantee the correct delivery of the dose to the patient. Bangladesh Journal of Physics, Vol. 29, Issue 2, pp. 59 – 67, December 2022

Droplet-based 3D bioprinting for drug delivery and screening.

Recently, the conventional criterion of "one-size-fits-all" is not qualified for each individual patient, requiring precision medicine for enhanced therapeutic effects. Besides, drug screening is a high-cost and time-consuming process which requires innovative approaches to facilitate drug development rate. Benefiting from consistent technical advances in 3D bioprinting techniques, droplet-based 3D bioprinting techniques have been broadly utilized in pharmaceutics due to the noncontact printing mechanism and precise control on the deposition position of droplets. More specifically, cell-free/cell-laden bioinks which are deposited for the fabrication of drug carriers/3D tissue constructs have been broadly utilized for precise drug delivery and high throughput drug screening, respectively. This review summarizes the mechanism of various droplet-based 3D bioprinting techniques and the most up-to-date applications in drug delivery and screening and discusses the potential improvements of droplet-based 3D bioprinting techniques from both technical and material aspects. Through technical innovations, materials development, and the assistance from artificial intelligence, the formation process of drug carriers will be more stable and accurately controlled guaranteeing precise drug delivery. Meanwhile, the shape fidelity and uniformity of the printed tissue models will be significantly improved ensuring drug screening efficiency and efficacy.

Enhanced siRNA Delivery with Novel Smart Chitosan-Based Formulations.

This study aims to develop an innovative multifunctional and dual responsive drug formulation for precise siRNA delivery to breast cancer sites, addressing the challenges posed by conventional cancer treatments which often result in adverse side effects due to their non-specific nature. The formulation made by incorporating gold coated superparamagnetic iron oxide nanoparticles (Au-SPIONs) into chitosan microspheres, which were subsequently loaded with siRNA. Comprehensive characterization, including scanning electron microscopy (SEM), transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier-transform infrared spectroscopy (FTIR), and energy-dispersive X-ray spectroscopy (EDS) confirmed the formulation's favourable morphology, particle size distribution, chemical composition, and stability, indicating its strong potential for effective siRNA drug delivery applications. The developed formulation demonstrated siRNA encapsulation efficiencies ranging from 27.4% to 88.6% and loading capacity from 0.291% to 1.59%, these values particularly higher for medium molecular weight chitosan. These results were compared across different formulations, showing that variations in chitosan type and crosslinker concentration significantly influenced encapsulation efficiency and drug release profiles. Additionally, our results were compared to previous studies on chitosan microspheres encapsulating organic drugs and siRNA, where the developed system demonstrated similar encapsulation and release properties.. The type of chitosan and the choice of crosslinker significantly influenced the drug release patterns. Diverse release profiles across batches highlighted the necessity for precise formulation control. Incorporating SPIONs into chitosan microspheres presents a promising strategy for magnetically driven, site-specific drug delivery. The dual pH-responsive and magnetic properties enable rapid and targeted siRNA release, leveraging the acidic tumor microenvironment as an internal stimulus in addition to external magnetic stimuli. This novel combination of SPIONs, chitosan microspheres, and siRNA encapsulation represents a new approach for targeted drug delivery. While further research is needed to refine and optimize this approach, our study provides a proof of concept for advancing targeted cancer therapies.

Light-activated photosensitizer/quercetin co-loaded extracellular vesicles for precise oral squamous cell carcinoma therapy.

Oral squamous cell carcinoma (OSCC) is the most common subtype of head and neck malignancies, characterized by a five-year survival rate that remains persistently below 50%, indicative of limited progress in therapeutic interventions. There is an urgent imperative to develop innovative therapeutic strategies, warranting the investigation of advanced treatment modalities. Nanocarriers offer a promising avenue by significantly enhancing drug properties and pharmacokinetics. Extracellular vesicles (EVs) are naturally occurring nanocarriers produced by cells and have become a focal point in drug delivery research. Quercetin, one of the most abundant dietary flavonoids, exhibits potent anticancer effects. However, its pharmaceutical application is hampered by poor water solubility, instability under physiological conditions, and low bioavailability. To overcome these obstacles, we propose using bio-derived EVs as carriers to co-encapsulate quercetin with the photosensitizer chlorin e6. This strategy leverages the intrinsic targeting capabilities of EVs for precise drug delivery to tumors, along with light-activated drug release, enabling rapid quercetin release under near-infrared light, effectively inhibiting cellular proliferation and inducing apoptosis in tumor cells. In vivo studies demonstrated that drug-loaded EVs exhibited robust tumor-targeting efficacy, resulting in effective and selective tumor ablation upon photoactivation in mice bearing subcutaneous MOC2 tumors.

Enhanced tumor self-targeting of lemon-derived extracellular vesicles by embedding homotypic cancer cell membranes for efficient drug delivery

Plant-derived nanovesicles (PDVs) as nanodrug delivery carriers have gained recognition due to their satisfactory biosafety. However, there remains a challenge to target tumor sites accurately due to the uncertain membrane protein components on the surface of vesicles. Herein, a composite nanodrug delivery system by encapsulating the chemotherapy drug DOX is establish to efficiently target breast cancer. The novel nanoplatform (LEVBD) is formed by embedding the membrane fragments from breast cancer cell with the lemon-derived nanovesicles (LEVs) as the foundational skeleton. LEVBD reveal wonderful homologous tumor targeting due to fusion of cancer cell membrane components with LEVs, and the encapsulation of hybrid vesicles facilitates the transcellular transport of drugs. After intravenous injection, LEVBD could efficiently and selectively home to homologous tumor sites even under competition from heterologous tumors and significantly inhibit tumor growth without any observable toxic side effects. The doping of homologous cancer cell membranes provides a paradigm for the precise delivery of drug delivery vehicles using plant-derived vesicles as the backbone.Graphical abstract

DNA-based Precision Tools to Probe and Program Mechanobiology and Organ Engineering.

DNA nanotechnology represents an innovative discipline that combines nanotechnology with biotechnology. It exploits the distinctive characteristics of deoxyribonucleic acid (DNA) to create nanoscale structures and devices with remarkable accuracy and functionality. Researchers may create complex nanostructures with precision and specialized functions using DNA's innate stability, adaptability, and capacity to self-assemble through complementary base-pairing interactions. Integrating multiple disciplines, known as nanobiotechnology, allows the production ofsophisticated nanodevices with a broad range of applications. These include precise drug delivery systems, extremely sensitive biosensors, and the construction of intricate tissue scaffolds for regenerative medicine. Moreover, combining DNA nanotechnology with mechanobiology provides anew understanding of how small-scale mechanical stresses and molecular interactions affect cellular activity and tissue development. DNA nanotechnology has the potential to revolutionize molecular diagnostics, tissue engineering, and organ regeneration. This could lead to enormous improvements in biomedicine. This reviewemphasizes the most recent developments in DNA nanotechnology, explicitly highlighting its significant influence on mechanobiology and its growing involvement in organ engineering. It provides an extensive overview of present trends, obstacles, and future prospects in this fast-progressing area.

Transportation using Drone

Abstract: This paper presents the design and proposed system will focus on designing drones capable of carrying lightweight to moderate payloads, equipped with advanced navigation systems and sensors to ensure safe and accurate delivery. It will integrate real-time obstacle detection, and automated landing systems for precision delivery. The drones will be managed through a centralized control system that coordinates flight paths, monitors battery status, and ensures compliance with air traffic regulations

Innovative Nano Delivery Systems for Astaxanthin: Enhancing Stability, Bioavailability, and Targeted Therapeutic Applications.

Astaxanthin (AST), as a natural antioxidant, has broad application prospects in medicine and health products. However, its highly unsaturated structure and significant lipophilic characteristics limit its dispersibility and bioavailability, thereby restricting its application in food, medicines, and nutraceuticals. To overcome these limitations, researchers have proposed the use of nano delivery systems. This review summarizes various nanocarriers, including liposomes, nanostructured lipid carriers, nanoparticles, and others, and analyzes their advantages in enhancing the solubility, stability, and bioavailability of AST. Furthermore, the study focuses on targeted delivery systems achieved through biomolecular modifications, which enable precise delivery of AST to specific cells or tissues, enhancing therapeutic effects. Additionally, smart-responsive delivery systems, such as pH-responsive and light-sensitive systems, are also discussed, showing their immense potential in precise release and targeted therapy. These findings provide new perspectives for the precise nutrition and clinical applications of AST. Future research should further optimize the design of nanocarriers to enable broader applications.

3D-printed radiopaque episcleral plaques with radioactive collimating cavities for enhanced dose delivery in brachytherapy.

Episcleral plaque brachytherapy (EPBT) is a well-established treatment. However, the lateral dose to healthy tissues, such as the sclera, retina, and optic nerve is often problematic and results in side effects. This study proposes an innovative approach based on the 3D-printing of radiopaque polymer plaques featuring cylindrical radioactive cavities (CRC) with a potential collimating effect on radiation delivery to tumors. A CAD model based on the COMS protocol was created and 3D-printed using radiopaque PEEK polymer. Cylindrical cavities (1 mm depth/diameter) were evenly spaced on the plaque's inner surface. Two radioactive layouts (RL1: uniform loading; RL2: radial gradient loading) were designed. µCT imaging was used to assess the geometric accuracy of the 3D-printed CRC EPs, and dose distribution was evaluated for the two (2) radioactive layouts using MAGIC-pf gel dosimetry and T2-weighted MRI. The resulting dose profiles were compared with those generated by both COMS and SEP plaques. Radiopaque CRC EPs showed higher central axis dose deposition while minimizing lateral overexposure compared to COMS and SEP plaques, while also providing robust back-shielding. Dose profiles from RL1 CRC EPs (uniform layout) extended deeper into the eye, whereas RL2 CRC EPs (with gradient) exhibited a more rapid dose fall-off, producing a concentrated, spherical dose distribution. 3D-printed radiopaque EPs with radioactivity encapsulated in cylindrical cavities demonstrated the ability to achieve more forward-projected dose profiles in EPBT. This fabrication design and a modulated radioactivity distribution across the EP surface would enable more precise and deeper dose delivery while reducing radiation exposure to lateral healthy tissues.

Precision Therapy for Prostate Cancer: Advancements in Polymeric Nanocarrier Systems.

Prostate cancer is a major worldwide health concern, and existing treatments often face challenges such as drug resistance, systemic toxicity, and insufficient targeting. Polymeric nanocarriers are currently employed as sophisticated tools in the field of oncology, offering the possibility to augment the administration and efficacy of anticancer therapies. In order to effectively eradicate prostate cancer, this review delves into the function of polymeric nanocarriers. Databases such as PubMed, ScienceDirect, and Google Scholar were utilized to do a comprehensive literature assessment. For this search, we used terms like "polymeric nanocarriers," "prostate cancer," "drug delivery," and "nanotechnology." Studies have shown that polymeric nanocarriers greatly improve the delivery and effectiveness of treatments for prostate cancer. Nanocarriers enhance the solubility, stability, and bioavailability of drugs, resulting in improved therapeutic effects. Functionalization using targeting ligands, such as folic acid and prostate-specific membrane antigen (PSMA) antibodies, has demonstrated the ability to enhance targeted specificity, resulting in a decrease in off-target effects and systemic toxicity. Polymeric nanocarriers facilitate precise and prolonged drug delivery, leading to elevated drug levels in tumor tissues. Polymeric nanocarriers are a notable breakthrough in the management of prostate cancer, providing precise medication administration, decreased toxicity, and improved therapy effectiveness. However, additional study is necessary to enhance the design of nanocarriers, evaluate their long-term safety, and enable their use in clinical applications. Continued interdisciplinary research and collaboration are essential for addressing current obstacles and maximizing the promise of polymeric nanocarriers in the treatment of prostate cancer.

Microneedles at the Forefront of Next Generation Theranostics.

Theranostics, combining therapeutic and diagnostic functions, marks a revolutionary advancement in modern medicine, with microneedle technology at its forefront. This review explores the substantial developments and multifaceted applications of microneedles, which have evolved from basic transdermal drug delivery devices to sophisticated diagnostic and therapeutic platforms. Microneedles enhance access to biomarkers via interstitial fluid, enabling real-time monitoring of physiological conditions, such as glucose and hormone levels, thus facilitating continuous health tracking. The evolution of microneedle design from solid to dissolvable forms broadens their utility from mere drug delivery to complex sensing and therapeutic applications, including insulin delivery for diabetes management, vaccination, and gene therapy. This paper delves into the integration of microneedles with wearable technologies, highlighting their role in closed-loop systems that combine real-time monitoring with dynamic, precise therapeutic delivery. By addressing gaps in the literature regarding their integrated diagnostic and treatment capabilities, this review underscores the pivotal role of microneedles in personalizing medicine. It concludes with a visionary perspective on the future trajectory of microneedle technology, emphasizing its potential to revolutionize therapeutic strategies through enhanced efficacy, safety, and patient compliance.

Rectifying the Crosstalk between the Skeletal and Immune Systems Improves Osteoporosis Treatment by Core-Shell Nanocapsules.

Contemporary osteoporosis treatment often neglects the intricate interactions among immune cells, signaling proteins, and cytokines within the osteoporotic microenvironment. Here, we developed core-shell nanocapsules composed of a cationized lactoferrin core and an alendronate polymer shell. By tuning the size of these nanocapsules and leveraging the alendronate shell, we enabled precise delivery of small interfering RNA targeting the Semaphorin 4D gene (siSema4D) to specific bone sites. This strategy integrates the antiresorptive drug alendronate with siSema4D, efficiently inhibiting osteoclast (OC) differentiation and bone resorption, while promoting osteogenesis to restore the balance between osteoblasts (OBs) and OCs. Moreover, encapsulating siSema4D within the nanocapsules helps to mitigate immunological cascades, thereby reversing the inflammatory microenvironment and restoring immune homeostasis and providing insights into the immunomodulatory effects of Sema4D in osteoporosis therapy. In both ovariectomized and senile osteoporotic mouse models, local intramuscular administration of core-shell nanocapsules effectively rectified the imbalance between the skeletal and immune systems, significantly enhancing the overall efficacy of osteoporosis treatment. Our findings underscore the therapeutic promise of addressing the multifaceted osteoporotic microenvironment through targeted interventions.