Periodic Reporting for period 2 - DIRNANO (Directing the immune response through designed nanomaterials)
Période du rapport: 2022-10-01 au 2024-09-30
The project deals with effective application of nanoparticles (NPs) for drug-gene delivery, therapy and diagnosis. Despite initial promises, NPs have proven to be under the expectations (relatively low patenting delivery and product market release). Although the success of anti-COVID nanovaccines has given some hope, we must understand the reasons of such difficulty. We focus on the innate ability of our body to scrutiny and clear NPs and improved the understand the chemical characteristics to ensure immunity evasion making an important progress in the direction of eliminating major obstacles for future nanotheranostic development.
Scientific objectives achieved:
- We improved the ability of NPs to be “invisible” by immune system by starting decoding the molecular logic used by the immune system to discriminate nanomaterial surface chemical properties, producing advanced immune-inert nanosystems or immune targeting/nano vaccines NPs.
- We contributed minimizing interspecies biases, so avoiding misleading preclinical-human extrapolations in NP medical translation by understanding species-specific NP immune recognition mechanisms and providing guide-lines to address preclinical-human patient mismatch, in the interactions with immune systems.
- We document the therapeutic efficacy of drug and photosensitizer-carrying NPs targeting cancer and tumor microenvironment immunosuppressive cells
- We improved the nanovaccine targeting of those cells triggering immune response (dendritic cells) by tumor neoantigens-coupled NPs and the antitumor nanovaccination efficacy by acting on both antigen and coats chemistry.
Scientific objectives achieved:
- We improved the ability of NPs to be “invisible” by immune system by starting decoding the molecular logic used by the immune system to discriminate nanomaterial surface chemical properties, producing advanced immune-inert nanosystems or immune targeting/nano vaccines NPs.
- We contributed minimizing interspecies biases, so avoiding misleading preclinical-human extrapolations in NP medical translation by understanding species-specific NP immune recognition mechanisms and providing guide-lines to address preclinical-human patient mismatch, in the interactions with immune systems.
- We document the therapeutic efficacy of drug and photosensitizer-carrying NPs targeting cancer and tumor microenvironment immunosuppressive cells
- We improved the nanovaccine targeting of those cells triggering immune response (dendritic cells) by tumor neoantigens-coupled NPs and the antitumor nanovaccination efficacy by acting on both antigen and coats chemistry.
We developed nano-assembling strategies ahead the present scenario using a large interdisciplinary scientist’s pool.
The in-depth functional study of the corona provided brand new information on unexcepted agonists of the human body which could direct NPs efficacy. We successfully identified NPs with decreased protein binding (e.g. polymer cyclization, dendrimer molecular spacing). In specific cases we spot human serum corona agonists. We prepared sets of NPs where selected chemical features candidate to be the targeted by sentinel proteins were tested in non-homogenous coats. We combined polymer conditioning of nanoparticle surfaces to achieve staple tightly-packed long-chain random-coil configuration to minimize statistical protein intercalation/binding. Several polymer types (linear, branched, dendrimer or cyclic), having variable length and/or charge have been conceived and synthesized in the network. Most of them are already part of NP coatings, and few are ready for this. Physisorption of model proteins or complex mixtures have been investigated after coating of bulk or nano-materials. In specific cases the creation of heterogeneous coatings, starting from such chemicals, have been studied in vitro to assess the effect on protein adsorption, complement activation in sera and their capture by phagocytes and dendritic cells.
We selected two lists of promising coating candidates for better stealthing nanosystems or better immune targeting/nano vaccines NPs. To introduce pathway-specific complement inhibitors we made considerable progress and identified human protein agonists acting on defined chemical coats. These are amenable for cloning, antibody production and mutation to down or up-modulate immune recognition and opsonization for phagocytes and immune-triggering dendritic cells.
In this perceptive we also studied possible misleading preclinical-human extrapolations in NP medical translation by understanding species-specific NP immune recognition mechanisms.
We successfully studied the therapeutic efficacy new peptide based nanovaccines for cancer treatment in preclinical models, and awe made significant progress in modulating tumor microenvironment immunosuppressive cells (e.g. TAM) and induce anti neoplastic cells effects using specific chitosan-based nanoformulations.
To improve the targeting of dendritic cells by tumor neoantigens-coupled NPs and the antitumor nanovaccination efficacy we had previously evaluated a first generation nanovaccine platform in a vaccination campaign, based on tumor specific peptides used as antigens. Eventually, we created new 2nd generation nano-vaccines with improved immune delivery and adjuvancy.
We have found that potential nanovaccine or therapeutically NPs with high Macrophage/DCs targeting not necessarily activate (adjuvant activity) cells (especially DCs) and found specific biochmeicla reasons for this lack of adjuvant effects.
The in-depth functional study of the corona provided brand new information on unexcepted agonists of the human body which could direct NPs efficacy. We successfully identified NPs with decreased protein binding (e.g. polymer cyclization, dendrimer molecular spacing). In specific cases we spot human serum corona agonists. We prepared sets of NPs where selected chemical features candidate to be the targeted by sentinel proteins were tested in non-homogenous coats. We combined polymer conditioning of nanoparticle surfaces to achieve staple tightly-packed long-chain random-coil configuration to minimize statistical protein intercalation/binding. Several polymer types (linear, branched, dendrimer or cyclic), having variable length and/or charge have been conceived and synthesized in the network. Most of them are already part of NP coatings, and few are ready for this. Physisorption of model proteins or complex mixtures have been investigated after coating of bulk or nano-materials. In specific cases the creation of heterogeneous coatings, starting from such chemicals, have been studied in vitro to assess the effect on protein adsorption, complement activation in sera and their capture by phagocytes and dendritic cells.
We selected two lists of promising coating candidates for better stealthing nanosystems or better immune targeting/nano vaccines NPs. To introduce pathway-specific complement inhibitors we made considerable progress and identified human protein agonists acting on defined chemical coats. These are amenable for cloning, antibody production and mutation to down or up-modulate immune recognition and opsonization for phagocytes and immune-triggering dendritic cells.
In this perceptive we also studied possible misleading preclinical-human extrapolations in NP medical translation by understanding species-specific NP immune recognition mechanisms.
We successfully studied the therapeutic efficacy new peptide based nanovaccines for cancer treatment in preclinical models, and awe made significant progress in modulating tumor microenvironment immunosuppressive cells (e.g. TAM) and induce anti neoplastic cells effects using specific chitosan-based nanoformulations.
To improve the targeting of dendritic cells by tumor neoantigens-coupled NPs and the antitumor nanovaccination efficacy we had previously evaluated a first generation nanovaccine platform in a vaccination campaign, based on tumor specific peptides used as antigens. Eventually, we created new 2nd generation nano-vaccines with improved immune delivery and adjuvancy.
We have found that potential nanovaccine or therapeutically NPs with high Macrophage/DCs targeting not necessarily activate (adjuvant activity) cells (especially DCs) and found specific biochmeicla reasons for this lack of adjuvant effects.
Our intention was speeding up the formulation of NPs, to reveal and treat high mortality human pathologies, so contributing to new technologies, based on NPs for mRNA delivery and gene therapy, with positive effects on the pharma-industry economy and social general well-being in the European area.
In the project we developed nano-assembling strategies ahead the present scenario. A set of branched, dendrimer layer-by-layer and cyclic polymer formulations, and lipid-based coats, and their combination in heterogenous ways, was under the focus of a large interdisciplinary scientist’s pool. This created a unique environment in itself. The in-depth functional study of the corona provided brand new information on unexcepted agonists of the human body which could direct NPs efficacy. We found compelling evidence of the ability of innate soluble and membrane bound agonists to bind Nanomaterial Associated Molecular Patterns (NAMPs) , and highlighted in specific cases the relevance of evaluating their different expression and specificity in preclinical models (muse and pig ) vs humans, providing tentative guide line to minimize the consequent possible translation failures connected to species-specific differences.
We characterised the nanoparticles candidates with best characteristics (coats, antigenicity and adjutancy) in vivo.
We obtain: 1) long-circulating stealth nanosystems outperforming the PEG-based, with interesting organ specific tropism. 2) nano-vaccine with strong neoplastic antigen display and entering Antigen Presenting Cells capture, to increase “antitumor vaccination” efficacy. TAM targetting is expected to implement double anti-tumor strategies.
We posed the base for the optimal progress of future project-works and career of young researchers in both industry/private and academic/public sectors in the European area.
We offered a Business School Class accompanying the rest of the project. ESRs benefited from the contact with R&Ds local and network-wide.
An intersectoral environment was achieved, through the implementation of foreseen actions, Intersectoral stage and collaborations. The parallel interdisciplinary and intersectoral formation of young researchers in this expanding technology, will contribute to the industrial and economic progress of the European area.
Articulated communication instruments and the outreach actions performed different publics and stake-holders will improve the awareness of society and next generations on the relevance of science and nanomedicine for socio-economic progress and human health. This will strengthen the possibility to grow new generations of scientists and businesswomen/men having a major understanding of science knowledge-based human progress.
Tens of papers have been published or are in an incubation stage. Two patent applications stemmed from our project so far.
In the project we developed nano-assembling strategies ahead the present scenario. A set of branched, dendrimer layer-by-layer and cyclic polymer formulations, and lipid-based coats, and their combination in heterogenous ways, was under the focus of a large interdisciplinary scientist’s pool. This created a unique environment in itself. The in-depth functional study of the corona provided brand new information on unexcepted agonists of the human body which could direct NPs efficacy. We found compelling evidence of the ability of innate soluble and membrane bound agonists to bind Nanomaterial Associated Molecular Patterns (NAMPs) , and highlighted in specific cases the relevance of evaluating their different expression and specificity in preclinical models (muse and pig ) vs humans, providing tentative guide line to minimize the consequent possible translation failures connected to species-specific differences.
We characterised the nanoparticles candidates with best characteristics (coats, antigenicity and adjutancy) in vivo.
We obtain: 1) long-circulating stealth nanosystems outperforming the PEG-based, with interesting organ specific tropism. 2) nano-vaccine with strong neoplastic antigen display and entering Antigen Presenting Cells capture, to increase “antitumor vaccination” efficacy. TAM targetting is expected to implement double anti-tumor strategies.
We posed the base for the optimal progress of future project-works and career of young researchers in both industry/private and academic/public sectors in the European area.
We offered a Business School Class accompanying the rest of the project. ESRs benefited from the contact with R&Ds local and network-wide.
An intersectoral environment was achieved, through the implementation of foreseen actions, Intersectoral stage and collaborations. The parallel interdisciplinary and intersectoral formation of young researchers in this expanding technology, will contribute to the industrial and economic progress of the European area.
Articulated communication instruments and the outreach actions performed different publics and stake-holders will improve the awareness of society and next generations on the relevance of science and nanomedicine for socio-economic progress and human health. This will strengthen the possibility to grow new generations of scientists and businesswomen/men having a major understanding of science knowledge-based human progress.
Tens of papers have been published or are in an incubation stage. Two patent applications stemmed from our project so far.