Alessandro Grattoni

Nanomedicine has progressed far beyond its early role as an experimental drug-carrier toolbox and today stands as a clinically validated enabling technology. Liposomal formulations and albumin-bound nanoparticles have transformed cancer therapy, while lipid nanoparticle (LNP) platforms accelerated the rapid development and global deployment of SARS-CoV-2 mRNA vaccines—demonstrating how nanoscale engineering can reshape therapeutic response, manufacturing speed, and public health impact. With these successes as foundation, the field is rapidly expanding into more sophisticated delivery systems including cell-hitchhiking nanoparticles, biomimetic multivalent vaccines, implantable immunotherapy depots, high-loading polymeric micelles, organ-targeted gene and RNA carriers, and bio-hybrid extracellular vesicle and mitochondrial therapies. These platforms aim not only to transport drugs, but to modulate immunity, direct regeneration, and enable precision intervention at the cellular and molecular scale. This perspective summarizes the current landscape of biomedical nanotechnologies and outlines how their continued evolution positions nanomedicine as an enabling science driving the next generation of therapeutics.

Pancreatic islet transplantation represents a promising therapeutic strategy for type 1 diabetes (T1D). In this context, the subcutaneous space offers a safer and more accessible alternative to the clinically established intraportal delivery route. However, a major unmet need remains the development of a site capable of supporting rapid vascularization and sustained islet function. In its current configuration, this approach is limited by poor vascularization, hypoxia-driven islet loss, loss of spatial control during graft delivery, and tissue disruption associated with delivery strategies. To address these challenges, the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device provides a prevascularized subcutaneous platform that supports islet viability and enables localized immunosuppressant delivery. In this study, we describe the incorporation of a 3D-printed removable placeholder into the NICHE platform to preserve a defined cavity within the device during prevascularization and enable subsequent islet delivery. The placeholder shapes the spatial organization of vascularized tissue, promoting uniform three-dimensional islet distribution upon transplantation. Surface characterization showed that polyamide and BioMed Clear resin exhibit distinct cell adhesion properties, enabling controlled tissue integration and atraumatic placeholder removal. Collectively, these results are consistent with preservation of vascularization, improved islet dispersion within the cell reservoir, reduced inflammatory cell infiltration, and support of metabolic function compared to injection-based delivery. These findings establish spatially controlled cell delivery within a prevascularized niche as a key design principle for enhancing engraftment efficiency and advancing the translational potential of subcutaneous islet transplantation for T1D and related cell-based therapies. Graphical abstract The alternative text for this image may have been generated using AI.

Pancreatic islets are essential for both clinical islet transplantation and preclinical studies aimed at understanding the mechanisms and progression of diabetes. However, progress in these fields is often limited by the availability of high-quality islets, as emerging therapeutic strategies require larger, cleaner, and more standardized preparations. This article presents a high-throughput, standardized protocol for surgical harvesting, enzymatic digestion, and density-gradient purification of pancreatic islets from Lewis rats. The method combines intraductal pancreas perfusion with a defined enzyme blend, pooled digestion of multiple pancreases, and density-based separation to maximize yield while minimizing fragmentation and eliminating the need for routine hand-picking. Islet yield is quantified using two complementary approaches: a traditional aliquot-based counting method commonly used in clinical settings, and a semi-automated whole-preparation imaging-based method. In a representative isolation from 12 pancreases, manual counting yielded approximately 3,300 islet equivalents (IEQ) and 2,700 absolute islets per pancreas (~39,600 total IEQ), with a size distribution of 62% (50-100 µm), 17% (100-150 µm), 10% (150-200 µm), 5% (200-250 µm), and 6% (>250 µm). In comparison, whole-prep automated analysis reported 16,350 total IEQ (1,362 IEQ/pancreas), highlighting inherent variability in aliquot-based quantification. Preparations had a purity of 98% by dithizone staining, and islet viability was maintained at 98% in vitro on days 3 and 7 after isolation. Functional assessment by static glucose-stimulated insulin secretion demonstrated a 10-fold increase in insulin release following a 1-h stimulation with 16.7 mM glucose. Overall, this protocol provides a reproducible and efficient approach for generating high-purity, functionally intact islet preparations that can be used immediately without additional cleanup. Islets retain robust function in culture for up to seven days, enabling flexibility for large-scale in vitro assays as well as in vivo transplantation studies.

Systemic immunosuppression remains essential for preventing allogeneic transplant rejection, but its chronic use causes substantial toxicity. Conceptually, local, site‐specific immunomodulation offers a promising alternative, yet comparative mechanistic insight into how immunosuppressants behave when delivered directly to the graft is lacking. Here, we leveraged the Neovascularized Implantable Cell Homing and Encapsulation (NICHE) device, a subcutaneous, vascularized cell‐encapsulation platform, as a spatially defined and reproducible model to study local immunomodulation in allogeneic islet transplantation. We systematically profiled the safety, local and systemic immunomodulatory effects, pharmacokinetics, and longitudinal biodistribution of five clinically relevant agents delivered locally at the graft site: CTLA4‐Ig, anti‐lymphocyte serum, anti‐CD40L, anti‐CD2, and anti‐IL6. Sustained in situ exposure did not impair islet viability or function, and immunosuppressants were confined within the graft, with up to 100‐fold lower systemic concentrations. Individual agents produced distinct immune signatures, spanning lymphocyte depletion and shifts in T‐cell activation that can guide rational, mechanism‐informed combinations for allogeneic cell transplantation. These findings provide a comparative framework for evaluating localized immunosuppression with the potential to transform immunoprotection in cell therapy.

A nanofluidic electrochemical pump uses in situ gas generation to modulate pressure and enable remotely controlled, on-demand drug release across diverse molecules.

Wireless power transfer (WPT) is a key enabler for long-term operation of implantable medical devices, eliminating the need for percutaneous drivelines and frequent surgical device replacements. This paper presents the design and validation of a fully wireless, rechargeable implantable drug delivery system (nDS) with an integrated power management and control system, specifically developed for use in freely moving animal models. The proposed system consists of a subcutaneous implant with an inductive power receiver and an external, backpack-mounted power transmitter that dynamically adjusts energy delivery in response to real-time implant feedback. A closed-loop power control strategy, implemented via Bluetooth Low Energy (BLE) communication, ensures adaptive power transfer to maintain system efficiency despite coil misalignment and animal movement. Building on a previously characterized inductive link, the present work extends the validation from benchtop characterization to in vivo operation in freely moving rats, demonstrating safe and repeatable wireless battery recharging of an implantable nanofluidic drug delivery system. Across four in vivo recharging sessions, the median average power transfer efficiency during constant-current phase was 22.9% with a median average power delivered to the load of 104.7 mW. The charging sessions lasted from 90 (first) to 30 (last) minutes, performed once per week over 4 weeks. The proposed closed-loop WPT implementation enabled reliable battery recharging within clinically relevant time scales while maintaining operation in compliance with thermal safety constraints, thereby supporting chronic, fully untethered drug delivery studies in small animals.