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The full therapeutic potential of nanomedicines is unfulfilled due to opposing interactions with body’s defenses and adverse immune reactions. Overcoming these obstacles requires a comprehensive understanding of nanomaterials-host interplay and an extensive animal model testing.
This project responds to such need by developing strategies to map, study, modulate and exploit nanoparticle (NP)-immune interactions through core state-of-the-art approaches.
1) inception of novel, but simple, coating engineering based on new organic polymers and conjugation chemistry, rational polymer pairing and zwitterionic lipids,
2) engineering (with a green-chemistry approach) of libraries of host or microbial derived modulators of the innate immunity (particularly of the complement system) and
3) designing and pre-clinical testing of next generation therapeutic nanovaccines (i.e. NPs with optimized multivalent neo-antigen presentation and immunostimulatory cues) and immunomodulating NPs directly targeting tumor cells or immune suppressive cells.
The DIRNANO’s core-scientific training is focused on gross structure-activity profiling, integrating interfacial and chemical sciences with systems immunology for mapping of dynamic host and interfacial factors that regulate NP performance.
This approach will lead to rational engineering of libraries of on-demand NPs with tunable immune modulating functions (exemplified in the pictogram). Moreover, the combinatorial analysis of NP core-coat scaffold will improve our temporal and spatial understanding of biomaterial-innate immune interactions at a deeper molecular level, and potentially fill the void in overcoming adverse injection reactions to nanopharmaceuticals in sensitive individuals.
The participating teams comprise internationally renowned scientists and industrialists at the forefront of nanomedicine, immune safety, pharmaceutical sciences, green chemistry, commerce and business, where many of the participants have a proven record of accomplishment and working with each other.
The program provides an integrated and highly interdisciplinary approach for academic and regulatory/business training of next-generation European Early Stage Researchers (ESRs) having a broader cutting-edge knowledge in translational nanomedicine bioengineering.
ESRs will master immune safe-by-design and pharmaceutically viable smart-by-design approaches to lead the development of the future nanopharmaceuticals through a low-risk-high gain perspective.
All-in-all, DIRNANO generates a unique pan-European macro-environment for integrated, advanced and accelerated training and circulation of ESRs through open innovation and outreach activities at the highest international level, thereby contributing to the European socioeconomics and education values, skill retention and brain-gain.
The H2020 funded project DIRNANO which stands for “Directing the immune response through designed nanomaterials” officially starts on October 1, 2020, for a four-years period and with a budget of more than 4 million EUR.
DIRNANO Consortium consists of twelve European partners and five participating organisations, coordinated by Prof. Emanuele Papini, Università degli Studi di Padova.
European participating organisations:
MAKING SCIENCE WITH DIRNANO
The body rejection of our nanomedical “gifts”
DIRNANO deals with a sort of “molecular misunderstanding” affecting the development of nanomedicine.
Nanoparticles for medical applications (diagnosis or therapy) are obviously intended to be “good” to our body. However, in most of cases, they are seen as “bad” by the body itself, intercepted and soon eliminated. This is often accompanied by adverse reactions.
Apparently, after decades of nano-investigation we realize that this is a major problem blocking nanomedicine full flowering. Why is it so? Are we in a cul-de-sac? Or can we find a way out?
With this project we want to understand the reasons for such an “evaluation error” made by body’s first-line defense-mechanisms, when they face all the possible extraordinary nanoparticles for medical applications we can imagine, design and synthesize thanks to the power of modern chemistry.
Its goal is avoiding such misunderstanding or, on the contrary, if it is convenient, exploiting it.
Disentangling the nano-magic bullet
Nanoparticles interpret very well the old notion of the so-called magic bullet: an object of the same size order of proteins, which can be designed to specifically target and deliver drugs to diseased cells (like tumor ones) for their elimination or cure, perfectly safe for the rest of the body. After many years, this exciting idea somewhat lost strength and is often discredited or considered a non-realizable dream. This is especially due to the high rate of development failure in the nanomedicine field.
DIRNANO core idea is that a major problem for nanomedicine full application is … us, the potential patients; or, more precisely, the way we cope with foreign and potentially dangerous materials or microorganisms.
Indeed, not only the adaptive immune system can elicit antibodies against nanoparticles, but, even more direct, rapid and possibly devastating is the action of innate immunity.
This is an evolutionary very old array of several germ-encoded proteins incessantly monitoring, we may say “touching”, any surface entering the body or created in it due to pathological mechanisms.
These innate patrolling proteins, like the lectins, want to soon understand if the corpuscles they encounter are potentially dangerous to the organism: this is their mission and they are relentless in doing this.
Once they have “decided” they can ignore the NPs or immediately neutralize it, for example by activating the complement and eventually leading to their rapid elimination from the body.
What do we know about these “strange” chemical-physical nature which are recognized by innate Pattern Recognition Molecules like dangerous?
Not much. We know that they can sense simple sugars or chemical group (N-acetyl, hydroxyl) with certain spatial disposition typical of microbes, but this is just the tip of the iceberg, and there are still unknown criteria used by these “innate antibodies” we simply still ignore.
The unexpected thing that is now emerging is that very frequently nanosystems surfaces, even when coated with polymers, supposed to confer bio-compatibility and to render the NP invisible (stealth) are misunderstood as if they were thing to be eliminated by the restless innate immune PRM.
Decoding the language of the innate NPs recognition and learning how to use it at our advantage.
With DIRNANO we have the ambition of understanding the logic underlying innate immunity recognition of NPs ant to identify the chemical features responsible for such recognition.
We have an evolutionary perspective in doing this job: it is very well known that innate recognition is still evolving and may adapt to the specific need of a given species (including the humans). Therefore, preclinical model species, like mouse, pig, or other very likely will respond to the same NPs particle differently than the human being. Interindividual differences can also take place, stressing the need of personalized understanding of NP-innate interactions.
But this is not all: what applications can benefit from the decodification of innate immunity NP affinity characteristics?
All in all, DIRNANO is just this: directing, as an orchestra director, the extent and the type of NP innate immunity interaction, from full avoidance to intentional favoring of their interaction, depending on the application: from fully stealth NPs to immune stimulating nano-vaccine.
A major application stemming from our molecular mapping of immune relevant determinants on NPs will be anti-tumor strategy base non-vaccination o targeting of TAM.
In our network we have universities teams and SMEs with outstanding capability of creating a plethora of nanoparticle core and surface arrays. Silica, poli-lipoic, chitosan, gold cores will be covered with systematic variants of linear or cyclic polymers, or lipidic molecules.
Academies and enterprises will dedicate to full specie-specific characterization of the host proteins interacting with the above NP set, including the innate agonists: this in humans and major preclinical models. Full proteomics and functional characterization of this proteome or corona will be tested with the help of molecular biology, monoclonal antibodies development and targeting, inhibitors.
At the end, precise information will lead to the design of fully stealth NPs. Or to NP favoring DCs or Tumor Associated Macrophages Targeting. Tumor targeting with nano-vaccine will be extensively studies in preclinical models.
Funded by the European Union.
This project has received funding from the European Union’s Marie Skłodowska –Curie actions (MSCA) that provide grants for all stages of researchers' careers.
Furthermore MSCA-ITNs support competitively selected joint research training and/or doctoral programmes, implemented by European partnerships of universities, research institutions, and non-academic organisations.
The research training programmes provide experience outside academia, hence developing innovation and employability skills. ITNs include industrial doctorates, in which non-academic organisations have an equal role to universities in respect of the researcher's time and supervision, and joint doctoral degrees delivered by several universities