Deep Tissue Research Articles

Cutaneous Immune Responses to Ablative Fractional Laser, Heat- and Cold-Based Dermatological Procedures.

Physical treatment modalities, such as ablative fractional laser (AFL), electrocautery, and cryotherapy, are extensively used in the field of dermatology. This study aimed to characterize the short-term innate and adaptive immune responses induced by AFL compared with heat- and cold-based procedures. Innate (CD11b+Ly6G+ neutrophils) and adaptive (CD8+CD3+ T cells) immune cell infiltration and histopathological changes were examined in murine skin on Days 1 and 7, following AFL, monopolar-electrocautery (RF), thermocautery, and cryotherapy. Interventions were standardized to reach the reticular dermis. Clinical skin reactions were photo-documented daily. As a comparator, the adaptive immune response was examined in murine basal cell carcinomas (BCC) on Day 7 after AFL exposure. Baseline histopathology confirmed immediate deep dermal tissue impact by all procedures. Immune cell dynamics varied across treatments throughout the progression of clinical and histopathological responses. On Day 1, AFL and heat-based procedures triggered an innate immune response, characterized by CD11b+Ly6G+ neutrophil cell infiltration that correlated with histopathological findings and immediate onset of clinical skin reactions. In addition, heat-based procedures led to an increase in overall dermal CD45+ cells (Day 1), which continued to rise for AFL and RF-electrocautery at Day 7 posttreatment. On the contrary, cryotherapy did not induce immediate (Day 1) innate immune responses, but instead a delayed increase in neutrophil and CD45+ cell infiltration (Day 7), which coincided with the late onset of clinical reaction. CD3+ T cells and CD8+CD3+ T cells demonstrated a similar pattern, with an increase observed for heat-based procedures on Day 1 and a delayed increase for cryotherapy on Day 7. Distinctive for AFL-treated skin, the level of dermal CD3+ T cells increased over time, significant by Day 7, and AFL-treated mouse BCCs responded with increased CD8+ T cell infiltration at Day 7 posttreatment. Heat- and cold-based procedures developed distinct cutaneous immune responses, with cryotherapy resulting in a delayed response compared to immediate immune responses from heat-based procedures. The substantial T cell response induced by AFL in the skin and BCC tumors indicates a potential for AFL as an adjuvant in immunotherapeutic treatments of keratinocyte cancers.

Molecular Imaging of Ovarian Follicles and Tumors With Near-Infrared II Bioconjugates.

Follicular tracking is typically conducted using ultrasound technology, but its effectiveness is constrained by limited resolution. High-resolution imaging of deep tissues can be accomplished using luminescence imaging in the near-infrared II window (NIR-II, 1000-1700nm); however, the contrast agents that are used lack specificity. Here, it is reported that the FDA-approved indocyanine green (ICG)-conjugated recombinant human chorionic gonadotropin (hCG) protein can target early follicles with long-term effectiveness. A novel high-resolution NIR-II imaging approach is developed for monitoring follicular development as well as ovulation using multi-color imaging of ovarian vessels with a combination of non-overlapping downconversion nanoparticles (DCNPs). The results showed that the ability to monitor early follicles of around 50µm in diameter exceeded the spatial and temporal resolution of ultrasound or MRI without the reproductive damage associated with computed tomography radiation, and this enabled the clinical identification of the follicular reserve in patients with infertility diseases such as polycystic ovary syndrome (PCOS). In addition, NIR-II imaging clearly targeted ovarian tumors and showed micro-metastatic lesions, thus providing a new tool for monitoring tumors in vivo and guiding surgical resection.

Photoacoustic Imaging of pH-Sensitive Optical Sensors in Biological Tissues

Photoacoustic imaging is an emerging biomedical imaging technique that enables non-invasive visualization of the optical absorption properties of biological tissues in vivo. Although numerous studies have used contrast agents to achieve high-contrast imaging in deep tissues, targeting specific areas remains a challenge when using agents that are continuously activated. Recent research has focused on developing triggered contrast agents that are selectively activated in target areas. This review delves into the use of pH-triggered contrast agents in photoacoustic imaging, which take advantage of the lower pH of the tumor microenvironment compared to normal tissues. The paper discusses the mechanisms of pH-triggered contrast agents that contribute to improving depth and contrast in photoacoustic tumor imaging. In addition, the integration of functionalities, such as photothermal therapy and drug delivery monitoring, into these agents demonstrates significant potential for biomedical applications.

Benign Glomus Tumor of the Urinary Bladder: A Case Report and Literature Review.

Glomus tumor is a rare neoplasm, typically found in superficial soft tissues and extremities, particularly in the subungual region. However, it can also occasionally affect deep soft tissue or viscera, such as the bladder, albeit infrequently. Our patient was a 51-year-old man presenting with recurrent hematuria of unknown etiology, accompanied by a blood clot that resolved spontaneously after 1 day. Abdominal computed tomography revealed multiple calculi in the right kidney, whereas cystoscopy showed mucosal edema on the left side of the bladder. A magnetic resonance image of the bladder identified an ovoid mass on the left side, measuring approximately 3.1 cm × 2.7 cm × 2.1 cm. This mass demonstrated a slightly increased signal intensity on T2-weighted images and an intermediate signal intensity on T1-weighted images. These findings suggested a malignant tumor in the urinary bladder with a nonfunctional right kidney. The patient underwent laparoscopic surgery to remove the right kidney and part of the bladder. Histologically, the tumor primarily consisted of round cells and abundant eosinophilic or pale cytoplasm. Immunohistochemical staining demonstrated diffuse positivity for smooth muscle actin and vimentin, and focal positivity for synaptophysin. The final pathological diagnosis was a bladder glomus tumor. At 15 months after resection, the patient was in good health with no recurrence or metastasis. The clinical manifestations and imaging features of bladder glomus tumors can pose diagnostic challenges for urologists. Therefore, it is imperative to consider this tumor in the differential diagnosis of bladder tumors and to enhance the understanding among urologists and pathologists regarding this entity.

Single-Frequency Birdcage Coils for Deep Tissue Perfluorocarbon Magnetic Resonance Imaging in Mice.

Fluorine-19 (19F) MRI has become an established tool for invivo cell tracking following exvivo or invivo labelling of various cell types with 19F perfluorocarbons (PFCs). Here, we developed and evaluated novel mouse-specific radiofrequency (RF) hardware for improved dual 1H anatomical imaging and deep tissue 19F MR detection of PFCs. Three linearly polarized birdcage RF coils were constructed-a dual-frequency 1H/19F coil, and a pair of single-frequency 1H and 19F coils, designed to be used sequentially. RF coil quality factors (Q values), signal homogeneity and sensitivity were benchmarked against a commercially constructed dual-frequency 1H/19F surface coil. RF homogeneity was assessed using a phantom designed to mimic PFC localization at depth in a mouse. The single-frequency birdcage coils (1H and 19F) displayed more uniform coverage and enhanced signal-to-noise ratios (SNRs) compared to both the birdcage and surface dual-frequency coils for 19F detection. Bilateral injection of a perfluoropolyether nanoemulsion into the footpads of female athymic nude mice, resulting in drainage to various lymph nodes and subsequent accumulation in lymph node macrophages, provided a platform to assess differences in SNRs and contrast-to-noise ratios (CNR) between both coil configurations as a function of depth and location. The single-frequency 1H coil provided significantly increased CNR in anatomical images (p < 0.001) with increased anatomical coverage compared to the dual-frequency surface coil. The single-frequency 19F birdcage coil offered increased PFC detectability with significantly higher SNR in renal, lumbar, sciatic and popliteal lymph nodes (p < 0.01) compared to the dual-frequency surface coil. Interestingly, the percentage difference between SNR measurements in lymph nodes between the single-frequency 19F coil and the 1H/19F surface coil had a linear relationship with increasing distance from the surface coil (R2 = 0.6352; p < 0.0001), indicating a potential disagreement for imaging experiments that rely on 19F spin quantification at increasing depth within the mouse using surface RF coils.

Upconversion Nanoparticle-Anchored Metal-Organic Framework Nanostructures for Remote-Controlled Cancer Optogenetic Therapy.

Optogenetics, a revolutionary technique utilizing light-sensitive proteins to control cellular functions with high spatiotemporal precision, presents a promising avenue for disease treatment; however, its application in cancer therapy remains constrained by limited research. Herein, we introduce a pioneering strategy for remote-controlled optogenetic cancer therapy, synergistically merging optogenetics with ion therapy, which incorporates ion self-supply, in situ ion channel construction, and near-infrared (NIR) light-activated ion therapy, facilitating remote and noninvasive manipulation of cellular activities in deep tissues and living animals. We report the facile synthesis of water-dispersible upconversion nanoparticle (UCNP)-metal-organic framework (MOF) nanohybrids capable of effectively delivering plasmid DNA to cancer cells, thereby enabling the in situ expression of photoactivatable cation channels. The pH-responsive MOF components serve as a reservoir for metal cations, which are released in the acidic microenvironment of tumors, while the UCNP components function as remote-controlled transducers, converting near-infrared (NIR) light into visible light to activate the cation channels and allowing the cancer influx of released metal cations for ion therapy. The proposed remote-controlled cancer optogenetic therapy demonstrates its effectiveness across multiple tumor models, including subcutaneous colon tumors, subcutaneous breast tumors, and orthotopic breast tumors. This study represents a significant step toward the realization of optogenetics in clinics, with substantial potential for advancing cancer therapy.

Clear Cell Sarcoma of the Parotid Gland: Case Report and Review of the Literature.

Clear cell sarcoma (CCS) of the parotid gland is a rare and aggressive cancer, predominantly affecting the deep soft tissues of the lower extremities, and is more frequently observed in the elderly. Its occurrence in the head and neck area, particularly in the parotid gland, is exceedingly rare. This study presents a 75-year-old male who exhibited a substantial, swiftly-enlarging mass on the left side of the mandible, which was diagnosed as CCS of the parotid gland. Morphologically and immunohistochemically, CCS shares characteristics with melanomas, and Ewing sarcoma, complicating differential diagnosis. The primary treatment for localized CCS typically involves surgical excision with clear margins. However, due to its resistance to conventional chemotherapy, there is ongoing research regarding the efficacy of adjuvant therapies such as chemoradiation, lymphadenectomy as well as immunotherapies such as immune checkpoint inhibitors. Further research is imperative to enhance our understanding of CCS and to develop more effective treatment strategies.

Endothelial molecule levels (VCAM-1, ICAM-1) in uncomplicated malaria cases in Lagos, Nigeria

Background. Elevated endothelial activation markers are linked to malaria syndromes due to the sequestration of Plasmodium falciparum-infected red blood cells in deep tissue vessels. This study evaluated vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) levels in uncomplicated malaria and their association with host factors. Methods. A cross-sectional study was conducted in four health facilities in Ikorodu, Lagos State, Nigeria. Blood samples from children and adults were screened for malaria via microscopy, and plasma ICAM-1 and VCAM-1 levels were measured using ELISA. Results. ICAM-1 (1.03 × 106 ± 20,689.2 pg/ml) and VCAM-1 (1.11 × 106 pg/ml; range: 3,725–6,273,725 pg/ml) levels were significantly higher in malaria-positive cases compared to controls (p &lt; 0.01). The geometric mean parasite density was 11,183 parasites/μl, but ICAM-1 and VCAM-1 levels did not correlate with parasite density (p &gt; 0.1). Packed cell volume (PCV) was significantly lower in malaria-positive cases (p = 0.042), with ICAM-1 and VCAM-1 negatively correlating with PCV (p &lt; 0.05). Both markers were also inversely associated with age (p &lt; 0.05). Conclusion. VCAM-1 and ICAM-1 levels are elevated in uncomplicated malaria, independent of parasite density but negatively associated with PCV and age, highlighting the role of endothelial activation in malaria pathology.

Wearable Single‐Electrode Capacitive Sensor with Large Penetration Depth for Intelligent Deep Tissue and Hemorrhage Monitoring

Wearable Single‐Electrode Capacitive Sensor with Large Penetration Depth for Intelligent Deep Tissue and Hemorrhage Monitoring

Molecular Engineering of Ultrabright Biomimetic NanoGhost for Site-Selective Tumor Imaging and Biodistribution.

Optically active ultrabright imaging agents are shown to delineate tumor location with deep tissue visualization in pre noclinical tumor models. NanoGhosts (NGs) particles are reconstructed from the cell membrane and integrated with organic fluorophores to attain ultra-brightness for solid tumor imaging. Moreover, the integration of amphiphilic and lipophilic molecules reveals structural characteristics of NGs (≈70nm), which also alter their brightness. Upon intravenous administration (10 mgkg-1 single dose), these ultrabright NGs (778 MESF) enable the high-resolution of tumor site and real-time tracking of vital organs with high-contrast fluorescence signals. Engineered biomimetic NGs demonstrates better resolution and tissue penetration as compared to the clinically approved indocyanine green (ICG). High precision in tumor detection (0.5h) and strong tumor retention (24h which is further up to 30th day) without affecting healthy tissues ensure the future scope of NGs in early-stage cancer imaging. These findings suggest that these NGs mimic the biological characteristics of native cells, enabling them to evade immune clearance and target the solid tumor naturally.

Portfolio of colloidally stable gold-gold sulfide nanoparticles and their use in broad-band photoacoustic imaging.

There is an increasing interest in non-invasive photoacoustic imaging and hence demand for non-toxic, stable, optical solid absorbers, particularly in the visible and near-infrared regions enabling deep tissue penetration. The most popular gold nanorods (GNR) suffer from cumbersome synthesis with poor reproducibility and stability under moderate laser exposure. Recently, a new class of nanoparticle, gold-gold sulfide (GGS), was recognized to have strong NIR absorption but lack colloidal stability. Here, we successfully synthesized a portfolio of aqueous GGS nanoparticles (NP) with excellent stability through a one-step, reproducible synthesis: Anionic, cationic, and protein-coated GGS NPs were obtained by using 3-mercaptopropionic acid (3MPA), branched poly(ethyleneimine) (bPEI) and bovine serum albumin (BSA) as a coating. All GGS NPs comprise small (<10 nm) and large anisotropic (>30 nm) morphologies and display two absorption bands centered at 530-540 nm and 800-900 nm. The photoacoustic activity (PA) of GGS NPs in solution at the visible (532 nm) and NIR (800 nm) region is similar and independent of the coating. Remarkably, they outperformed the spherical gold NPs and performed comparable to GNRs. In vitro PA microscopy images recorded with visible and NIR lasers revealed that GGS NPs are successfully internalized by triple-negative MDA-MB-231 breast cancer cells, used for the proof of principle. A coating-dependent intracellular PA signal in favor of GGS-3MPA was observed. The weakest signal was obtained with the GGS-BSA, indicating a low cellular uptake. These stable, aqueous GGS NPs emerge as promising candidates for broad-band PAI and further biomedical applications.

Primary Intraosseous Solitary Fibrous Tumor of the Mandible: Report of a Diagnostically Challenging Case with NAB2::STAT6 Fusion and Review of the Literature.

Solitary fibrous tumor (SFT) represents an uncommon mesenchymal neoplasm affecting primarily the extremities and deep soft tissues with, overall, benign but locally aggressive biologic behavior and an underlying pathognomonic NAB2::STAT6 fusion. Intraosseous SFTs are infrequent, and involvement of the jawbones is exceedingly rare. A 54-year-old woman presented with an asymptomatic, well-demarcated, multilocular radiolucency of the left posterior mandible featuring focally irregular borders, root resorption and lingual cortex perforation. The lesion had shown progressive growth over a 6-year period. Microscopically, a proliferation of predominantly ovoid and spindle-shaped cells with indistinct cell membrane borders, elongated, plump or tapered, hyperchromatic nuclei, and lightly eosinophilic cytoplasm was noted. Marked cytologic atypia, pleomorphism and mitoses were absent. A secondary population of epithelioid cells exhibiting ovoid or elongated vesicular nuclei, and abundant, pale eosinophilic or vacuolated cytoplasm was also present. The supporting stroma was densely fibrous with areas of marked hyalinization and variably-sized, ramifying, thin-walled vessels. By immunohistochemistry, lesional cells were strongly and diffusely positive for STAT6 and CD99, and focally immunoreactive for MDM2 and SATB2. Ki-67 was expressed in less than 5% of lesional cells, while most interspersed epithelioid cells were positive for the histiocyte marker, CD163. Molecular analysis disclosed a NAB2::STAT6 fusion confirming the diagnosis of SFT. The patient underwent segmental mandibulectomy. Herein, we report the first case of primary intraosseous SFT of the mandible with complete documentation of its characteristic immunohistochemical and molecular features. Diagnosis of such unusual presentations may be further complicated by the challenging histomorphologic diversity of SFT.

Probing Deep Hydrogen Polysulfides Fluctuations In Vivo by Engineering Activatable Fluorescence Reporters with Second Near-Infrared Window Emission.

Deep and comprehensive understanding of the intricate biochemical processes mediated by H2Sn (n ≥ 1), but not H2S, is of paramount importance. A few fluorescent probes have been developed with the intention of addressing this issue. However, there is currently no evidence of any activatable NIR-II fluorescent probes for H2Sn-specific imaging over H2S. In this study, we developed the inaugural H2Sn-activated NIR-II probe for specific and deep imaging of H2Sn through a series of molecular engineering strategies. Strong electron-absorbing moieties enabled the redshift of the emission of the designed reporter, while leaving groups with different dissociation capacities were responsible for modulating the selective and sensitive responsiveness to H2Sn over H2S. By using this activatable specific probe for deep tissue mapping of endogenous H2Sn fluctuations, accurate identification of acute inflammation in animal models was achieved. It is anticipated that the advancement of this activatable NIR-II probe will facilitate a more profound comprehension of the physiological implications of H2Sn.

Phage-liposome nanoconjugates for orthopedic biofilm eradication

Infection by multidrug-resistant (MDR) bacteria has become one of the biggest threats to public health worldwide. One reason for the difficulty in treatment is the lack of proper delivery strategies into MDR bacterial biofilms, where the thick extracellular polymeric substance (EPS) layer impedes the penetration of antibiotics and nanoparticles. Here, we propose a novel bioactive nanoconjugate of drug-loaded liposomes and bacteriophages for targeted eradication of the MDR biofilms in orthopedic infections. Phage Sb-1, which has the ability to degrade EPS, was conjugated with antibiotic-loaded liposomes. Upon encountering the biofilm, phage Sb-1 degrades the EPS structure, thereby increasing the sensitivity of bacteria to antibiotics and allowing the antibiotics to penetrate deeply into the biofilm. As a result, effective removal of MDR bacterial biofilm was achieved with low dose of antibiotics, which was proved in this study by both in vitro and in vivo investigations. Notably, in the rat prosthetic joint infection (PJI) model, we found that the liposome-phage nanoconjugates could effectively decrease the bacterial load in the infected area and significantly promote osteomyelitis recovery. It is therefore believed that the conjugation of bacteriophage and liposomes could open new possibilities for the treatment of orthopedic infections, possibly other infections in the deep tissues.

Conservative Tangential Excision Instead of Escharotomy in the treatment of Compartment Syndrome

Purpose: One of the primary causes of heat-induced compartment syndrome is the loss of elasticity of the body surface eschar itself, we have recently replaced escharotomy with conservative tangential excision in the treatment of compartment syndrome caused by heat and achieved good results.Methods: Since 2019, our burn center has applied conservative tangential excision and heterogeneous dermal coverage technology for decompression treatment of 16 patients with thermal-induced compartment syndrome, involving 19 parts of the limbs and 5 parts of the chest and abdomen. All cases were treated with decompression under general anesthesia within 12-48 hours after burn.Results: All patients were treated with conservative tangential excision for decompression. After limb decompression, the peripheral blood supply was restored, and the obvious pulse could be touched. No further fasciotomy was performed, and no secondary damage of deep muscle, nerve and vascular tissue was found in the follow-up treatment; After thoracic and abdominal decompression, there was no respiratory restriction and circulatory disorder.Conclusion: Conservative tangential excision represents an effective method for both the prevention and treatment of heat-induced compartment syndrome, it can be used as an alternative method for escharotomy.

Microwave-responsive two-dimensional materials for microwave therapy of deep tissue diseases

Microwave-responsive two-dimensional materials for microwave therapy of deep tissue diseases

Nanoparticle-enhanced near-infrared fluorescence probes as a new frontier in cancer imaging

Recent advancements in nanotechnology have significantly enhanced the development of near-infrared fluorescence (NIRF) probes, positioning them as powerful tools in cancer imaging. This paper explores the unique advantages of nanoparticles incorporating NIR dyes, such as indocyanine green (ICG) and DiR, which exhibit deep tissue penetration and minimal background autofluorescence. The enhanced permeability and retention (EPR) effect facilitates selective accumulation in tumor tissues, enabling sophisticated imaging and precision-targeted drug delivery systems. This review highlights the remarkable potential of NIRF imaging techniques in molecular diagnostics, emphasizing their ability to differentiate malignant tissues at a molecular level. Additionally, we discuss various NIRF dye classifications, including cyanine and BODIPY-based probes, along with the development of multifunctional agents that enhance imaging specificity and therapeutic effectiveness. The integration of advanced targeting capabilities, including the use of antibodies and small molecules, further improves the precision of these imaging agents. While challenges remain regarding the pharmacokinetics and potential toxicity of nanoparticle-based probes, their capacity for real-time tumor tracking and the promise of multimodal imaging approaches underscore their transformative role in cancer diagnostics and treatment. By advancing the field of theranostics, nanoparticle-enhanced NIRF probes pave the way for personalized medicine and improved patient outcomes in oncology.

How does ali satia graha and thai massage method compare? Study on pain and range of motion of chronic ankle injury

Background and Study Aim. Chronic ankle injury is a common problem that results in prolonged pain and limited range of motion (ROM). This study aims to compare the effectiveness of Ali Satia Graha Method of Sports Injury Therapy Masage with Thai Massage in reducing pain and increasing ROM in chronic ankle injuries. Material and Methods. This study used a Quasi Experiment design with Two Group Pretest and Posttest Design. The subjects in this study were determined by perposive sampling technique, so a sample of 30 male patients aged 25-50 years was taken. Where the patient has a chronic ankle injury. In this study the subjects were given treatment in the form of sports injury massage therapy with the Ali Satia Graha and Thai Massage methods. The instrument in this study is a numeric rating scale (NRS) for pain measurement and a goniometer with units of degrees for range of motion. Analysis in this study was assisted by using the SPSS version 26 application. Results. The results showed a value of F = 7.370 p = 0.001, which indicates a significant difference between the two methods. The results of the analysis showed that the Ali Satia Graha Method of Sports Injury Therapy Masage was more effective than Thai Massage in reducing pain and increasing overall ROM, including plantarflexion and dorsiflexion. Ali Satia Graha's Massage technique, which combines friction and effleurage, provides deep tissue stimulation and helps to significantly reduce local inflammation. In contrast, Thai Massage excels at rapidly increasing joint flexibility through emphasis on acupressure pathways and active stretching. Conclusion. Based on these findings, the Ali Satia Graha method of massage therapy is recommended as a primary option in healing chronic ankle injuries, specifically to reduce pain and improve ROM.

Injectable, in-situ forming, tunable, biocompatible gelatin hydrogels for biomedical applications.

Gelatin hydrogels have drawn attention for their diverse biomedical applications due to their flexible physiochemical properties. However, such gelatin hydrogels are made of toxic crosslinkers and photoinitiators, restricting their non-invasive deep tissue application. The in-situ forming chemical crosslinked without such toxic crosslinker and UV light has not been explored under physiological conditions. This study establishes a simple method to fabricate an injectable click-chemistry-based in-situ forming gelatin hydrogel in a physiological environment (without toxic UV or photoinitiator) with tunable physiochemical properties to modulate cellular response. Using Divinyl Sulfone (DVS) modification, gelatin hydrogel (GelVS) is optimized with tunable degradation properties, moduli (100 Pa -1000 Pa), gelation time, swelling, degradation, and viscoelastic behaviour. The in-vitro results using fibroblast and stem cells show that the hydrogel and its precursors were cytocompatible with diverging feedback of cells as the modulus varies. The in-vivo analysis for injectability, degradation, and biocompatibility of the GelVS hydrogel displays their biocompatible nature and lasts up to 30 days at the injecting site. Overall results indicate that DVS-modified GelVS hydrogel will be a great system with tunable physicochemical properties to modulate favorable cellular response for tissue regeneration and non-invasive deep tissue application.

Vector-Free Deep Tissue Targeting of DNA/RNA Therapeutics via Single Capacitive Discharge Conductivity-Clamped Gene Electrotransfer.

Viral vector and lipid nanoparticle based gene delivery have limitations around spatiotemporal control, transgene packaging size, and vector immune reactivity, compromising translation of nucleic acid (NA) therapeutics. In the emerging field of DNA and particularly RNA-based gene therapies, vector-free delivery platforms are identified as a key unmet need. Here, this work addresses these challenges through gene electrotransfer (GET) of "naked" polyanionic DNA/mRNA using a single needle form-factor which supports "electro-lens" based compression of the local electric field, and local control of tissue conductivity, enabling single capacitive discharge minimal charge gene delivery. Proof-of-concept studies for "single capacitive discharge conductivity-clamped gene electrotransfer" (SCD-CC-GET) deep tissue delivery of naked DNA and mRNA in the mouse hindlimb skeletal muscle achieve stable (>18 month) expression of luciferase reporter synthetic DNA, and mRNA encoding the reporter yield rapid onset (<3 h) high transient expression for several weeks. Delivery of DNAs encoding secreted alkaline phosphatase and Cal/09 influenza virus hemagglutinin antigen generate high systemic circulating recombinant protein levels and antibody titres. The findings support adoption of SCD-CC-GET for vaccines and immunotherapies, and extend the utility of this technology to meet the demand for efficient vector-free, precision, deep tissue delivery of NA therapeutics.