Current challenges for the clinical advancement of nanoparticles

Despite advances in the nanomedicine market, there is still a considerable imbalance between academic research and clinical application in the field of nanomedicine [121]. Because nanomaterial performance is tightly linked to physicochemical properties, clinical translation depends on the development of robust, reproducible manufacturing and characterization processes [30]. At the same time, biological interactions, such as immune responses, and environmental considerations pose substantial challenges to nanomedicine development [25,176,181]. In addition, limited harmonization among regulatory frameworks across agencies may increase the complexity of clinical translation [57].

According to leading companies in the biotechnology sector, as reported by Clogston et al. [147], the main barriers limiting advancement include challenges related to manufacturability and scalability (40 %), development timelines (24 %) and installed capacity (18 %). Building on this industrial perspective, the following sections complement this view by including challenges discussed in the academic literature, offering a more comprehensive overview.

Challenges in industrial-scale manufacturing

A major challenge in the clinical translation of nanoparticle-based therapeutics concerns large-scale production, which is often hindered by difficulties in process standardization. This affects the reproducibility and economic feasibility of industrial nanoparticle manufacturing. The inherent complexity of these drug delivery systems, typically composed of multiple components, introduces both technical and economic barriers that slow the development of marketable products [141,182-184].

Specific issues include inadequate in-process quality control, the absence of industrial-scale equipment, difficulties in purification, high production costs, low yield, limited infrastructure and technical expertise, all of which are further aggravated by insufficient financial investment [185].

While efficient techniques already exist for the large-scale manufacturing of materials such as liposomes, the challenges increase significantly as systems become more complex. The incorporation of surface modifications, targeting elements or the encapsulation of multiple therapeutic agents requires several production steps. This not only increases costs but also complicates quality control and compromises stability [182,185]. Furthermore, investment in custom instrumentation, manufacturing equipment and facilities may be prohibitively expensive for some companies or may require staggered investment strategies contingent upon achieving incremental clinical development milestones, thereby extending timelines [182].

The challenges associated with industrial-scale production are not only critical themselves but also influence other obstacles in the clinical translation of nanoparticles. In particular, the ability to scale up functionalization processes is essential for innovations that aim to modify nanoparticles for better targeting or altered biodistribution [186].

In addition, scaling up manufacturing processes in compliance with good manufacturing practices (GMP) is critical to ensure both technical robustness and regulatory conformity, thereby guaranteeing the consistent quality and safety of the final drug product [187]. This interdependence emphasizes the need for an integrated and multifactorial approach to address the complexities of nanomedicine industrialization.

Challenges related to long-term stability

Significant challenges are associated with the long-term stability of nanostructured preparations, as they may lose activity within relatively short timeframes, ranging from weeks to months. Currently, some of these formulations require storage and transport under frozen conditions to maintain their functionality. Overcoming these limitations is essential to reduce costs and logistical complications related to cold-chain management [188,189]. Research on lyophilization has shown promising results as a potential solution, allowing these nanoparticles to be stored at ambient or even elevated temperatures while retaining bioactivity [190-192].

Challenges related to selective accumulation

Selective accumulation of nanoparticles remains a major challenge, as a considerable fraction of nanomedicines tends to accumulate uncontrollably in non-target organs, thereby reducing therapeutic efficiency. Elucidating the mechanisms governing nanoparticle transport may guide the development of formulations with improved accumulation efficiency at specific sites and, thereby, enhance clinical translation [193].

The surface of nanoparticles can be modified with ligands that recognize and bind to specific receptors present in target tissues, thereby facilitating accumulation at the desired site [194,195]. However, the potential of functionalization for active targeting may be limited by a lack of selective expression of the receptors targeted by nanoparticles. Additionally, the added ligands may be masked by the protein corona once in systemic circulation, concealing their targeting effects [193].

Factors such as the composition, size and shape of the base nanoparticles also influence their biological behaviour, including their blood circulation profile, site-specific accumulation and ability to penetrate tissues and specific cells [116,196].

Active targeting also depends on overcoming challenges such as nanoparticle stability in circulation, evasion of immune responses [197,198] and the ability to traverse biological barriers such as the blood-brain barrier [172,193]. It also involves the development of systems capable of responding to microenvironmental changes or external stimuli to achieve controlled drug release [70]. The complexity of addressing these challenges is further amplified by interpatient and tissue variability, which can affect therapeutic uniformity and efficacy [199].

Challenges in preclinical predictive models

One of the major challenges in the clinical translation of nanomedicine lies in the lack of preclinical models that accurately represent the heterogeneity of human diseases and their specific interactions with nanoparticle systems. This gap frequently results in a disconnection between preclinical outcomes and clinical performance, particularly affecting the early evaluation of safety and therapeutic efficacy [200,201].

It has been observed that nanoparticle-based drugs tend to exhibit lower predictability in their clinical behaviour during preclinical evaluation than conventional pharmaceuticals. This variability may arise from the critical influence of pharmacokinetic parameters, tissue distribution, accumulation and penetration at the target site and drug release within the target tissue, or even within target cells [202].

The chronic toxicity of nanomaterials, both at the cellular and systemic levels, must be carefully monitored to ensure the absence of long-term adverse effects. Such toxicity may vary depending on particle size, shape and composition, highlighting the need for strategies to evaluate and mitigate these potential risks [185,203].

Emerging evaluation strategies, such as organ-on-a-chip platforms, hold promise for reducing the gap between current preclinical models and in vivo behaviour [204], thereby contributing to improved clinical translation because of better predictive models.

Regulatory approval challenges

Within the specific area of regulatory approval, several authors have noted that regulation surrounding nanoparticles faces major challenges due to the lack of clear standards and adequate regulatory frameworks. Globally, regulatory agencies such as the FDA and the European Medicines Agency (EMA) still operate under traditional frameworks that may not be fully sufficient to ensure the quality and safety of nanomaterials. However, excessive regulation can also hinder innovation and increase approval costs [57,185].

International cooperation is essential to establish global standards for the regulation of nanoparticles in the biomedical field, ensuring their production under GMP. In addition, new analytical techniques are needed to assess their physical properties, along with standardized procedures to guarantee efficacy and safety [185].

The FDA maintains that its current regulatory framework is sufficiently robust and flexible to accommodate materials of different nature, including nanomaterials. These are therefore evaluated under existing regulatory guidelines [183]. Nonetheless, the agency acknowledges the need to reassess current classification systems and to develop dedicated tools for this field. Among its recommendations are the establishment of close collaboration between industry, academia and international organizations, the development of specific toxicological assessment assays and a deeper understanding of the correlation between physicochemical properties and in vivo biological behaviour [183].

Intellectual property challenges

Intellectual property challenges in nanomedicine stem from the fact that these developments often involve multiple aspects that may be subject to protection: (i) the encapsulated drug; (ii) the carrier technology; and (iii) the combined characteristics of the drug-carrier system, along with any additional modifications to the base vehicle. This complexity poses challenges in patent approval, especially when novel components are combined with previously protected elements. Such scenarios often necessitate cross-licensing agreements and multiple overlapping patents covering the same technology [185,205].

This issue can be exacerbated by the indiscriminate accumulation of patent filings, which may delay innovation approval, a practice known as patent thickets, and by the issuance of invalid patents. The complexity of intellectual property management in nanotechnology can lead to costly litigation that delays commercialization. Therefore, the development of international standards and policies specifically addressing intellectual property issues in health-related nanotechnologies is urgently needed [185,206].

Translational barriers in nanomedicine involve complex, multifactorial aspects that demand a multidisciplinary approach [183]. Shan et al. propose a framework to address these challenges by organizing them into strategic blocks aligned with the drug life cycle. This framework, shown in Figure 5, emphasizes the need to integrate technological innovation with appropriate regulatory frameworks. Together, these elements highlight the importance of cross-disciplinary integration to effectively advance nanomedicine from the nanoscale to the clinic.

Figure 5.: Perspectives for Addressing the Challenges in the Clinical Translation of Nanomedicine. The figure summarizes the integrated framework proposed by Shan et al. to address key translational challenges across the nanomedicine life cycle, spanning rational and patient-centred design, scalable and reproducible manufacturing, improved preclinical model relevance, regulatory alignment, and expansion toward new clinical indications. Reproduced from [193] under the Creative Commons Attribution 4.0 International License