Olga Khorkova, Claes Wahlestedt
The NANOSPRESSO project, described by Senti et al. in their lead article (Senti et al. 2025), is being developed to address the immense unmet medical need in the rare disease and rare cancers communities that are currently underserved by pharmaceutical industry and healthcare providers. The current situation in rare diseases, with small patient numbers (sometimes with only a single case reported worldwide) and substantial drug development costs, makes it difficult for the pharmaceutical companies to recoup their investment in this field.These commercial disincentives, combined with an uncharted regulatory landscape, impede the translation to the clinic of the scientific advances in development of nucleic acid-based therapeutics (NBTs) achieved in recent years that could have already significantly improved the lives of many patients with rare diseases and some rare cancers (Cheerie et al. 2023, Qian et al. 2025, Khorkova et al. 2023).Although the exact proportion of genetic diseases treatable by formulated NBTs (fNBTs) potentially produced by NANOSPRESSO is hard to calculate, a rough estimate based on the known types of pathogenic mutations and the proportions of genes amenable to regulation by multiple endogenous mechanisms that can be engaged by NBTs shows that it could be significant. However, in spite of the plethora of known NBT-based approaches that can be used in the treatment of genetic diseases caused by point mutations or insertions/deletions, substantial current practical challenges in this field can limit their impact (see Supplementary Materials).Although the first successful example of an "n=1" NBT (i.e., one produced for a single individual) was published in 2019 (Kim et al. 2019) it has not been widely replicated, with only 26 other cases over 16 years (Cheerie et al. 2025), and the currently available NBT treatments mostly focus on more common cases (e.g., nusinersen for spinal muscular atrophy) (Moultrie et al. 2025). The interdisciplinary team needed for development of such personalized medicines would require members with expertise in diagnosing the diseases, sequencing the mutations, designing and manufacturing NBTs to pharmaceutical standards, resolving patent issues, ensuring regulatory compliance, and administering the treatmentwith all of this provided in time to stop the progression of the disease. Assembling such a team for each individual case in limited available time is practically impossible under current conditions. This process however could be facilitated if there were institutions providing the necessary infrastructure, such as organizations capable of all the above functions.Establishing and financing such institutions represents probably the biggest challenge in translation of achievements in personalized medicine to the clinic. Other problems in this case include the need for regulatory bodies to develop the appropriate framework for personalized drugs and maintain specialized personnel for inspections, as well as multiple other legal and societal implications including treatment cost, patent issues, and ethical considerations.Senti et al. propose the NANOSPRESSO project as a solution to the challenges posed by translation of personalized NBTs to the clinic (Senti et al. 2025). NANOSPRESSO promotes decentralized personalized production of formulated NBTs, construed as drugs for magistral preparation in hospital pharmacies. Magistral preparation is used for individual patients when no approved alternatives exist, which is the case in many rare diseases.Senti et al. outline a production protocol that includes encapsulation of NBTs in lipid nanoparticles (LNPs) using microfluidics technology on location at hospital pharmacies. The NBTs will have to be custom-designed for individual patients, or small groups of patients.This could represent the most labor-intensive, unpredictable, and expensive step in the production process. The designed NBTs will then be manufactured at pharmaceutical-grade nucleic acid synthesis facilities (potentially including CelluTx LLC, siTOOLs Biotech, or Anjarium Biosciences AG). The authors envision that the final step of NBT drug manufacture, its encapsulation in LNPs (potentially designed and manufactured by companies such as Lipoid or NanoVation Therapeutics), will be accomplished at the hospital pharmacies using a specialized piece of microfluidics equipment (potentially by Solstice Act (FDCA) exempts pharmacy compounding performed for a specific patient from FDCA requirements such as compliance with current good manufacturing practices (cGMP), appropriate labeling, and US Food and Drug Administration (FDA) approval. However, due to complex and innovative nature of NBTs the regulatory bodies may need to develop the appropriate framework for personalized NBTs and maintain purpose-trained personnel for routine inspections of facilities in hospital pharmacies. Importantly, the authors stress their on-going communication with European and state regulatory authorities (Senti et al. 2025).Notably, the NANOSPRESSO project considers the implications of the patent laws, ethical considerations around gene editing and the implications for social equity and human diversity, all of which are essential for the wide adoption of personalized NBTs. Notably, the NANOSPRESSO project also plans to develop a unified platform for technology and data sharing with blockchain security and consistent data formats across the network. Such platform can ensure patient privacy and intellectual property protection and provide easy interface with AI tools.The current NANOSPRESSO-NL project is supported by a Netherlands Science Agenda-Netherlands Organization for Scientific Research grant. However, it is only a 6-year project, which does not allow sufficient time given the scope of the undertaking. Other financing sources may be available. Notably, the potential market for personalized drug technology is substantial, as more than 300 million people worldwide suffer from genetic disorders (The Lancet Global Health, 2024, Cavaller-Bellaubi et al. 2023). Additionally, new genetic disease-and cancer-causing mutations are discovered every year. From the reimbursement point of view, treatment with NBTs could significantly decrease lifelong spending compared to the currently available treatments. For example, average inpatient admission costs over a 12 month period post treatment with nusinersen (an NBT for spinal muscular atrophy (SMA))were reduced by 63% in pediatric patients and by 79% in adult patients as compared to the 12 months pre-nusinersen treatment with prior standard care (Zhu et al. 2024). Treatment with single injection gene therapy drug for SMA, onasemnogene abeparvovec, further reduced the annual numbers of inpatient admissions (by 66%) and emergency department visits (by 50%) compared to nusinersen treatment (Toro et al. 2023). These numbers are especially significant given that direct non-healthcare informal cost for families of SMA patients can reach 63% of total annual disease cost (Landfeldt et al. 2023;López-Bastida et al. 2017).Experience gained in the NANOSPRESSO project may help obtain a more realistic estimate of the benefits afforded by personalized drugs.Furthermore, data and expertise gained in the treatment of rare diseases could be instrumental in developing drugs for common diseases. The 'intervention-outcome' type datasets in uniform format generated by NANOSPRESSO could be essential for training AI tools for discovery of novel gene-disease associations, structure-activity relationships, assessing delivery efficiency of the LNP formulations and toxicity of NBTs, etc. Reports on drug preparation procedures and treatment outcomes provided by clinics utilizing the NANOSPRESSO approach are likely to be an important asset generated by the NANOSPRESSO program. Licensing access to data and reports generated in the NANOSPRESSO project to pharmaceutical and biotechnology companies could provide revenue to extend the project beyond the current 6-year funding period. However, fundraising (and associated expenses) may be needed to engage these and other financing sources, including rare disease foundations, charitable organizations, and government programs.At present the NBT treatments might not lead to a complete cure, due to late diagnoses, incomplete knowledge of disease biology, poor delivery to target tissues, suboptimal dosing regimens, toxicity, immunogenicity, etc. However, these issues can be resolved with more experience using NBTs in the clinic. Importantly, even in their current form, NBTs can bring significant improvements in patients' and caregivers' quality of life and relief to the financial burden (Zhu et. al 2024, Toro et al. 2023).As significant as the challenges with magistral production of personalized fNBTs are, they are surmountable given the measures proposed by NANOSPRESSO. Furthermore, as Senti et al. point out, there are successful precedents of personalized technologies being used at the point of care, e.g., the Prodigy system (Miltenyi Biotec, Inc) that automated the entire process of chimeric antigen receptor (CAR)-T cell manufacturing from cell activation to reinfusion.The NANOSPRESSO project could also tap into a pro-active network of rare disease foundations. Notably, NANOSPRESSO could enhance community participation by improving their website and posting frequent updates on the project plans, progress, crowdsourcing efforts and citizen scientists' initiatives, as the website could be the project's