Autophagy as a therapeutic target in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterised by early metastasis and resistance to anti-cancer therapy, leading to an overall poor prognosis. Despite continued research efforts, no targeted therapy has yet shown meaningful efficacy in PDAC; mutations in the oncogene KRAS and the tumour suppressor TP53, which are the most common genomic alterations in PDAC, have so far shown poor clinical actionability. Autophagy, a conserved process allowing cells to recycle altered or unused organelles and cellular components, has been shown to be upregulated in PDAC and is implicated in resistance to both cytotoxic chemotherapy and targeted therapy. Autophagy is thus regarded as a potential therapeutic target in PDAC and other cancers. Although the molecular mechanisms of autophagy activation in PDAC are only beginning to emerge, several groups have reported interesting results when combining inhibitors of the extracellular-signal-regulated kinase/mitogen-activated protein kinase pathway and inhibitors of autophagy in models of PDAC and other KRAS-driven cancers. In this article, we review the existing preclinical data regarding the role of autophagy in PDAC, as well as results of relevant clinical trials with agents that modulate autophagy in this cancer.

Effect of stroma on the behavior of temoporfin-loaded lipid nanovesicles inside the stroma-rich head and neck carcinoma spheroids.

BACKGROUND: Despite the highly expected clinical application of nanoparticles (NPs), the translation of NPs from lab to the clinic has been relatively slow. Co-culture 3D spheroids account for the 3D arrangement of tumor cells and stromal components, e.g., cancer-associated fibroblasts (CAFs) and extracellular matrix, recapitulating microenvironment of head and neck squamous cell carcinoma (HNSCC). In the present study, we investigated how the stroma-rich tumor microenvironment affects the uptake, penetration, and photodynamic efficiency of three lipid-based nanoformulations of approved in EU photosensitizer temoporfin (mTHPC): Foslip® (mTHPC in conventional liposomes), drug-in-cyclodextrin-in-liposomes (mTHPC-DCL) and extracellular vesicles (mTHPC-EVs). RESULTS: Collagen expression in co-culture stroma-rich 3D HNSCC spheroids correlates with the amount of CAFs (MeWo cells) in individual spheroid. The assessment of mTHPC loading demonstrated that Foslip®, mTHPC-DCL and mTHPC-EVs encapsulated 0.05 × 10- 15 g, 0.07 × 10- 15 g, and 1.3 × 10- 15 g of mTHPC per nanovesicle, respectively. The mid-penetration depth of mTHPC NPs in spheroids was 47.8 µm (Foslip®), 87.8 µm (mTHPC-DCL), and 49.7 µm (mTHPC-EVs), irrespective of the percentage of stromal components. The cellular uptake of Foslip® and mTHPC-DCL was significantly higher in stroma-rich co-culture spheroids and was increasing upon the addition of serum in the culture medium. Importantly, we observed no significant difference between PDT effect in monoculture and co-culture spheroids treated with lipid-based NPs. Overall, in all types of spheroids mTHPC-EVs demonstrated outstanding total cellular uptake and PDT efficiency comparable to other NPs. CONCLUSIONS: The stromal microenvironment strongly affects the uptake of NPs, while the penetration and PDT efficacy are less sensitive to the presence of stromal components. mTHPC-EVs outperform other lipid nanovesicles due to the extremely high loading capacity. The results of the present study enlarge our understanding of how stroma components affect the delivery of NPs into the tumors.

Methodological guide for assessing the carbon footprint of external beam radiotherapy: A single-center study with quantified mitigation strategies.

Background and purposes: Data on the carbon footprint of external beam radiotherapy (EBRT) are scarce. Reliable and exhaustive data, including a detailed carbon inventory, are needed to determine effective mitigation strategies. Materials and methods: This study proposes a methodology for calculating the carbon footprint of EBRT and applies it to a single center. Mitigation strategies are derived from the carbon inventory, and their potential reductions are quantified whenever possible. Results: The average emission per treatment and fraction delivered was 489 kg CO2eq and 27 kg CO2eq, respectively. Patient transportation (43 %) and the construction and maintenance of linear accelerators (LINACs) and scanners (17 %) represented the most significant components. Electricity, the only energy source used, accounted for only 2 % of emissions.Derived mitigation strategies include a data deletion policy (reducing emissions in 30 years by 12.5 %), geographical appropriateness (-12.2 %), transportation mode appropriateness (-9.3 %), hypofractionation (-5.9 %), decrease in manufacturers' carbon footprint (-5.2 %), and an increase in machine durability (-3.5 %). Conclusion: Our findings indicate that a significant reduction in the carbon footprint of a radiotherapy unit can be achieved without compromising the quality of care.This study provides a methodology and a starting point for comparison and proposes and quantifies mitigation strategies, paving the way for others to follow.

Restricted Net Treatment Benefit in oncology.

OBJECTIVES: The restricted Net Treatment Benefit (rNTB) is a clinically meaningful and tractable estimand of the overall treatment effect assessed in randomized trials when at least one survival endpoint with time restriction is used. Its interpretation does not rely on parametric assumptions such as proportional hazards, can be estimated without bias even in the presence of independent right-censoring, and can include a prespecified threshold of minimal clinically relevant difference. To demonstrate that the rNTB, corresponding to the NTB during a predefined time interval, is a meaningful and adaptable measure of treatment effect in clinical trials. METHODS: In this simulation study, we tested the impact on the rNTB value, estimation, and power of several factors including the presence of a delayed treatment effect, minimal clinically relevant difference threshold value, restriction time value, and the inclusion of both efficacy and toxicity in the rNTB definition. The impact of right censoring on rNTB was assessed in terms of bias. rNTB-derived statistical tests and log rank (LR) tests were compared in terms of power. RESULTS: RNTB estimates are unbiased even in case of right-censoring. rNTB may be used to estimate the benefit/risk ratio of a new treatment, for example, taking into account both survival and toxicity and include several prioritized outcomes. The estimated rNTB is much easier to interpret in this context compared to NTB in the presence of censoring since the latter is intrinsically dependent on the follow-up duration. Including toxicity increases the test power when the experimental treatment is less toxic. rNTB-derived test power increases when the experimental treatment is associated with longer survival and lower toxicity and might increase in the presence of a cure rate or a delayed treatment effect. Case applications on the PRODIGE, Checkmate-066, and Checkmate-067 trials are provided. CONCLUSIONS: RNTB is an interesting alternative to describe and test the treatment's effect in a clear and understandable way in case of restriction, particularly in scenarios with nonproportional hazards or when trying to balance benefit and safety. It can be tuned to take into consideration short- or long-term survival differences and one or more prioritized outcomes.

Reconstruction with antibiotic loaded single-side gore-tex "Tartine" methyl-methacrylate cementoplasty for pediatric chest wall reconstruction: A 10-case series.

INTRODUCTION: Chest wall reconstruction in children after large resection of tumors may be performed with rigid or soft materials. Cementoplasty is commonly used with the "Sandwich" method i.e. gore-tex meshes surrounding both faces of the cement. HYPOTHESIS: Is antibiotic loaded single-side gore-tex "Tartine" methyl-methacrylate cementoplasty an interesting alternative to the double-side "sandwich" method for chest wall reconstruction? MATERIAL AND METHODS: Consecutive patients who were treated from 2011 to 2023 in our hospital were included. RESULTS: Among the ten children treated with a median 5.6 years follow-up, there were no surgical complications related to the reconstruction, loss of function, infections, post operative complications (versus 22.7% in meta-analysis encompassing the 50 rigid reconstructions reported worldwide) nor scoliosis (versus 25%). Three patients have an asymmetric chest wall appearance. DISCUSSION: "Tartine" cementoplasty is a simple, low-cost technique for pediatric chest wall reconstruction. It is well tolerated and checks key demands for chest wall reconstructions. LEVEL OF EVIDENCE: IV; retrospective case series.

Intraperitoneal Nivolumab After Debulking Surgery and Hyperthermic Intraperitoneal Chemotherapy in Advanced Ovarian Cancer: A Phase I Study with Expansion Cohort.

PURPOSE: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are expected to be synergistic with intraperitoneal (IP) immunotherapy by increasing tumor antigen expression and mutational load. We assessed the feasibility and safety of IP nivolumab following complete CRS and HIPEC in pretreated patients with recurrent ovarian cancer (ClinicalTrials.gov identifier: NCT03959761). PATIENTS AND METHODS: Patients received IP nivolumab (0.5, 1 and 3 mg/kg) using a 3+3 dose-escalation design, starting 5-7 days after CRS and HIPEC. Four IP Q2W nivolumab infusions were planned. The primary objective was to demonstrate the feasibility of IP nivolumab based on dose-limiting toxicity (DLT). Secondary objectives were to assess changes in tolerance of CRS and HIPEC. RESULTS: A total of 17 patients were enrolled including 10 patients in the dose-escalation and 7 patients in the expansion phase. No DLT was observed at any dose-level in the 9 evaluable patients. Six of the 17 patients (35%) did not complete all planned infusions: 4 (23.5%) due to peritoneal catheter complications, 2 (11.8%) due to early progression. No procedure-related deaths occurred. Eleven patients (65%) experienced serious adverse events (SAEs), mainly transitory grade 3-4 transaminases elevations (6/11), and surgery-related (9/11). Four SAEs were related to the peritoneal catheter and two to HIPEC. No SAEs/grade 3-4 adverse events related to IP nivolumab occurred. CONCLUSIONS: This is the first study demonstrating the feasibility of IP nivolumab in patients with relapsed advanced ovarian cancer; further investigation at 3 mg/kg is warranted.

Hybrid extracellular vesicles for drug delivery.

Extracellular vesicles (EVs) are expected to serve as interesting drug delivery vectors as they may offer unique and new properties for drug delivery. Their natural origin, protein and nucleic acid composition, and intrinsic pleiotropic therapeutic effects could enable new possibilities in the field of drug delivery. Here, we aimed to review the methods used to produce Hybrid EVs, a recently emerged type of EV-based vector made from both EVs and synthetic vectors to exploit their respective properties. Hybrid EV/synthetic objects can be obtained by incubation, electrostatic interactions, polyethylene glycol (PEG)-mediated fusion, co-extrusion, freeze-thawing, or simple EV surface modification, leading to different types of objects. We also opted to review the properties of these vectors, and specifically compared them with those of other drug delivery vectors. It has to be noticed that only a limited number of study report loading metrics that allow cross article comparison. Based on this critical analysis, we attempted to draw the pith and marrow from these relatively difficult-to-compare studies and integrate them into the more general context of opportunities in drug delivery and drug development, with a particular focus on oncology.

Arthroscopic Suture-Saucerization of Discoid Meniscus Allows Volume Conservation but Does Not Fully Restore Coverage.

Purpose: The purpose of this study was to quantify the effect of meniscoplasty suture-saucerization on volume and surface coverage of lateral discoid menisci. Methods: This retrospective study included all consecutive 10 patients treated between 2014 and 2019 who had magnetic resonance imaging before and after surgery and 15 controls. The MITK 3M3 semiautomatic software was used to segment the meniscus and cartilage before and after surgery to measure the percentage of meniscus coverage on the tibial cartilage. Results are compared to control patients without knee pathology matched on sex and age with Student t test. Results: Discoid meniscus surface and volume before surgery were respectively 597 mm2 (range, 550-887 mm2) and 2,822 mm³ (1,571-3,407 mm³), representing 74.5% (56%-89%) of the tibial cartilage surface. After surgery, it decreased to 422 mm2 (229-569 mm2) and 1,235 mm³ (680-1,738 mm³), leading to 45.7% (22.5%-68.6%) coverage. In the control group, median surface was 457 mm2 (314-641 mm2), volume was 1,321 mm3 (641-2,240 mm3), and tibial coverage was 55% (41%-77%). Altogether, meniscus volume after surgery was similar to normal, while coverage was significantly lower than controls (P = .04). Conclusions: Meniscoplasty suture-saucerization procedure may allow meniscus sparing and restauration of a similar to normal meniscus volume. Meniscus surface and coverage are diminished compared to controls. Both surface and volume normalization is usually not achievable without decreasing the thickness of the rather thick discoid meniscus. Clinical Relevance: Both surface and volume normalization is usually not achievable without decreasing the thickness of thick discoid menisci.

Medical oncologist stereotypes among medical students, residents and physicians: a national cross-sectional study.

OBJECTIVES: The perception of oncologists could impact the attractiveness of the specialty and dialogue between oncologists and other physicians. The aim of the study was to describe and understand the stereotypes and social representation (SR) associated with oncologists among medical students, residents and physicians in France. METHODS: This nationwide web-based survey conducted in 2021 was based on hierarchical evocation methods. Qualitative analyses were based on the Reinert method with factorial analyses. Each respondent's SR was graded from 1 to 5 (from 1: very positive SR to 5: very negative SR). RESULTS: Oncologists suffer from a rather negative SR. The negative representation was mostly related to difficulties in practising and the proximity with death and end of life. Oncologists were also associated with more positive notions like interdisciplinarity or intellectual complexity. Attendance to an oncology course was associated with a better SR of oncology (p=0.036), whereas having someone in the family practising oncology had a negative impact (p=0.028). CONCLUSIONS: SR of oncologists is rather contrasted. It was positively influenced by attendance to an oncology course, which could be an option to correct stereotypes and update on this rapidly evolving specialty.

Generation of Hybrid Extracellular Vesicles by Fusion with Functionalized Liposomes.

Extracellular vesicles (EVs) and liposomes are natural and synthetic drug delivery systems, respectively, with their own advantages and limitations. EV/liposome fusion allows the generation of hybrid EVs that benefit from both the versatility of liposomes (tunable lipid and protein composition, surface functionalization, lumen loading, etc.) and the functionality of EVs (natural targeting properties, low immunogenicity, anti-inflammatory properties, etc.). Here, we describe the methods to (1) produce EVs and liposomes, (2) induce and monitor their fusion, and (3) purify the obtained hybrid EVs.

Thinking Quantitatively of RNA-Based Information Transfer via Extracellular Vesicles: Lessons to Learn for the Design of RNA-Loaded EVs.

Extracellular vesicles (EVs) are 50-1000 nm vesicles secreted by virtually any cell type in the body. They are expected to transfer information from one cell or tissue to another in a short- or long-distance way. RNA-based transfer of information via EVs at long distances is an interesting well-worn hypothesis which is ~15 years old. We review from a quantitative point of view the different facets of this hypothesis, ranging from natural RNA loading in EVs, EV pharmacokinetic modeling, EV targeting, endosomal escape and RNA delivery efficiency. Despite the unique intracellular delivery properties endowed by EVs, we show that the transfer of RNA naturally present in EVs might be limited in a physiological context and discuss the lessons we can learn from this example to design efficient RNA-loaded engineered EVs for biotherapies. We also discuss other potential EV mediated information transfer mechanisms, among which are ligand-receptor mechanisms.

[Therapeutic applications of extracellular vesicles]. / Applications thérapeutiques des vésicules extracellulaires.

Extracellular vesicles, secreted spontaneously or in response to stress by all cell types, are proposed as alternative biotherapies to cellular therapies and to synthetic nanomedicines. Their logistical advantages (storage, stability, availability, tolerance), their ability to cross biological barriers, to deliver their contents (proteins, lipids and nucleic acids) in order to modify their target cells, as well as their immunomodulatory and regenerative activities, are of growing interest for a very wide spectrum of diseases. Here we review the challenges to bring these biotherapies to the clinic and discuss some promising applications in cancer and regenerative medicine.

TITLE: Applications thérapeutiques des vésicules extracellulaires. ABSTRACT: Les vésicules extracellulaires, sécrétées spontanément ou en réponse à un stress par tous les types cellulaires, sont proposés comme des biothérapies alternatives aux thérapies cellulaires et aux nanomédicaments synthétiques. Leurs atouts logistiques (stockage, stabilité, disponibilité, tolérance), leur capacité à franchir les barrières biologiques, à délivrer leurs contenus (protéines, lipides et acides nucléiques) pour modifier leurs cellules cibles, ainsi que leurs activités immunomodulatrice et régénérative, suscitent un intérêt grandissant pour un très large spectre de maladies. Cette synthèse présente les défis qui restent à relever pour appliquer ces biothérapies en clinique. Quelques applications prometteuses dans les domaines du cancer et de la médecine régénérative seront proposées.

Technological advances towards extracellular vesicles mass production.

Extracellular vesicles (EVs) are becoming essential actors in bio-therapeutics, as much for their regenerative or immunomodulatory properties as for their potential as cargo delivery vehicles. To enable the democratization of these EV-based therapies, many challenges remain such as large-scale production which is necessary to reduce costs of treatment. Herein, we review some advanced works on high-yield EV manufacturing. One approach consists in developing large-scale cell culture platforms, while others focus on cell stimulation to increase particle yield per cell. This can be done by moderate physico-chemical stresses or by disrupting cell membrane towards autoassembled vesicle-like particles. We critically compare these different techniques, keeping in mind that the field still lacks shared characterization standards, underline the importance of therapeutic potency assessment and discuss mass production strategies that have been identified in current clinical trials.

Engineering and loading therapeutic extracellular vesicles for clinical translation: A data reporting frame for comparability.

Extracellular vesicles (EVs) have emerged as new drug delivery systems as well as a regenerative cell-free effectors going beyond academic research to reach industrial research and development (R&D). Many proof-of-concept studies are now published describing the delivery of drugs, nanoparticles or biologics among which nucleic acids, proteins, viruses, etc. Their main interests rely on their intrinsic biocompatibility, targeting capabilities and biological activities. The possibility of loading EVs with exogenous therapeutic drug/nanoparticles or imaging tracers opens up the perspectives to extend EV therapeutic properties and enable EV tracking. Clinical translation is still hampered by the difficulty to produce and load EVs with large scale, efficient and cGMP methods. In this review, we critically discuss important notions related to EV engineering and the methods available with a particular focus on technologies fitted for clinical translation. Besides, we provide a tentative data reporting frame in order to support comparability and standardization in the field.

Extracellular vesicles from adipose stromal cells combined with a thermoresponsive hydrogel prevent esophageal stricture after extensive endoscopic submucosal dissection in a porcine model.

In this study, we investigated the combination of extracellular (nano) vesicles (EVs) from pig adipose tissue-derived stromal cells (ADSCs) and a thermoresponsive gel, Pluronic® F-127 (PF-127), to prevent stricture formation after endoscopic resection in a porcine model. ADSC EVs were produced at a liter scale by a high-yielding turbulence approach from ADSCs 3D cultured in bioreactors and characterized in terms of size, morphology and membrane markers. The thermoresponsive property of the PF-127 gel was assessed by rheology. The pro-regenerative potency of ADSC EVs was investigated ex vivo in esophageal biopsies under starvation. In vivo tests were performed in a porcine model after extended esophageal endoscopic mucosal dissection (ESD). Pigs were randomized into 3 groups: control (n = 6), gel (n = 6) or a combination of 1.45 × 1012 EVs + gel (n = 6). Application of gel ± EVs was performed just after ESD with a follow-up finalized on day 21 post-ESD. There was a trend towards less feeding disorder in the EV + gel group in comparison with the gel and the control groups (16.67% vs. 66.7% vs. 83.33%, respectively) but without reaching a statistically significant difference. A significant decrease in the esophageal stricture rate was confirmed by endoscopic, radiological and histological examination for the EV + gel group. A decrease in the mean fibrosis area and larger regenerated muscularis mucosae were observed for the EV + gel group. In summary, the application of EVs + gel after extended esophageal endoscopic resection succeeded in preventing stricture formation with an anti-fibrotic effect. This nano-therapy may be of interest to tackle an unmet medical need considering that esophageal stricture is the most challenging delayed complication after extended superficial cancer resection by endoscopy.

Local administration of stem cell-derived extracellular vesicles in a thermoresponsive hydrogel promotes a pro-healing effect in a rat model of colo-cutaneous post-surgical fistula.

Extracellular vesicles (EVs), especially from stem/stromal cells (SCs), represent a cell-free alternative in regenerative medicine holding promises to promote tissue healing while providing safety and logistic advantages in comparison to cellular counterparts. Herein, we hypothesize that SC EVs, administered locally in a thermoresponsive gel, is a therapeutic strategy for managing post-surgical colo-cutaneous fistulas. This disease is a neglected and challenging condition associated to low remission rates and high refractoriness. Herein, EVs from a murine SC line were produced by a high-yield scalable method in bioreactors. The post-surgical intestinal fistula model was induced via a surgical cecostomy communicating the cecum and the skin in Wistar rats. Animals were treated just after cecostomy with PBS, thermoresponsive Pluronic F-127 hydrogel alone or containing SC EVs. A PET-monitored biodistribution investigation of SC EVs labelled with 89Zr was performed. Fistula external orifice and output assessment, probe-based confocal laser endomicroscopy, MRI and histology were carried out for therapy follow-up. The relevance of percutaneous EV administration embedded in the hydrogel vehicle was indicated by the PET-biodistribution study. Local administration of SC EVs in the hydrogel reduced colo-cutaneous fistula diameter, output, fibrosis and inflammation while increasing the density of neo-vessels when compared to the PBS and gel groups. This multi-modal investigation pointed-out the therapeutic potential of SC EVs administered locally and in a thermoresponsive hydrogel for the management of challenging post-surgical colon fistulas in a minimally-invasive cell-free strategy.

Development of extracellular vesicle-based medicinal products: A position paper of the group "Extracellular Vesicle translatiOn to clinicaL perspectiVEs - EVOLVE France".

Extracellular vesicles (EV) are emergent therapeutic effectors that have reached clinical trial investigation. To translate EV-based therapeutic to clinic, the challenge is to demonstrate quality, safety, and efficacy, as required for any medicinal product. EV research translation into medicinal products is an exciting and challenging perspective. Recent papers, provide important guidance on regulatory aspects of pharmaceutical development, defining EVs for therapeutic applications and critical considerations for the development of potency tests. In addition, the ISEV Task Force on Regulatory Affairs and Clinical Use of EV-based Therapeutics as well as the Exosomes Committee from the ISCT are expected to contribute in an active way to the development of EV-based medicinal products by providing update on the scientific progress in EVs field, information to patients and expert resource network for regulatory bodies. The contribution of our work group "Extracellular Vesicle translatiOn to clinicaL perspectiVEs - EVOLVE France", created in 2020, can be positioned in complement to all these important initiatives. Based on complementary scientific, technical, and medical expertise, we provide EV-specific recommendations for manufacturing, quality control, analytics, non-clinical development, and clinical trials, according to current European legislation. We especially focus on early phase clinical trials concerning immediate needs in the field. The main contents of the investigational medicinal product dossier, marketing authorization applications, and critical guideline information are outlined for the transition from research to clinical development and ultimate market authorization.

mTHPC-Loaded Extracellular Vesicles Significantly Improve mTHPC Diffusion and Photodynamic Activity in Preclinical Models.

Extracellular vesicles (EVs), derived from the cell, display a phospholipid bilayer membrane that protects the cargo molecules from degradation and contributes to increasing their stability in the bloodstream and tumor targeting. EVs are interesting in regard to the delivery of photosensitizers (PSs) used in the photodynamic therapy (PDT), as they allow us to overcome the limitations observed with liposomes. In fact, liposomal formulation of meta-tetra(hydroxyphenyl)chlorin (mTHPC) (Foslip®), one of the most potent clinically approved PSs, is rapidly destroyed in circulation, thus decreasing in vivo PDT efficacy. mTHPC-EV uptake was evaluated in vitro in a 3D human colon HT-29 microtumor and in vivo study was performed in HT-29 xenografted mice. The obtained data were compared with Foslip®. After intravenous injection of the mTHPC formulations, biodistribution, pharmacokinetics and PDT-induced tumor regrowth were evaluated. In a 3D model of cells, mTHPC-EV uptake featured a deeper penetration after 24h incubation compared to liposomal mTHPC. In vivo results showed a considerable improvement of 33% tumor cure with PDT treatment applied 24h after injection, while 0% was observed after Foslip®/PDT. Moreover, 47 days were required to obtain ten times the initial tumor volume after mTHPC-EVs/PDT compared to 30 days for liposomal mTHPC. In conclusion, compared to Foslip®, mTHPC-EVs improved mTHPC biodistribution and PDT efficacy in vivo. We deduced that a major determinant factor for the improved in vivo PDT efficacy is the deep mTHPC intratumor penetration.

Extracellular vesicles for personalized medicine: The input of physically triggered production, loading and theranostic properties.

Emerging advances in extracellular vesicle (EV) research brings along new promises for tailoring clinical treatments in order to meet specific disease features of each patient in a personalized medicine concept. EVs may act as regenerative effectors conveying endogenous therapeutic factors from parent cells or constitute a bio-camouflaged delivery system for exogenous therapeutic agents. Physical stimulation may be an important tool in the field of EVs for personalized therapy by powering EV production, loading and therapeutic properties. Physically-triggered EV production is inspired by naturally occurring EV release by shear stress in blood vessels. Bioinspired physically-triggered EV production technologies may bring along high yield advantages combined to scalability assets. Physical stimulation may also provide new prospects for high-efficient EV loading. Additionally, physically-triggered EV theranostic properties brings new hopes for spatio-temporal controlled therapy combined to tracking. Technological considerations related to EV-based personalized medicine and the input of physical stimulation on EV production, loading and theranostic properties will be overviewed herein.