Smart drug delivery systems to overcome drug resistance in cancer immunotherapy

Cancer immunotherapy,a therapeutic approach that inhibits tumors by activating or strengthening anti-tumor immunity,is currently an important clinical strategy for cancer treatment;however,tumors can develop drug resistance to immune surveillance,resulting in poor response rates and low therapeutic efficacy.In addition,changes in genes and signaling pathways in tumor cells prevent susceptibility to immunotherapeutic agents.Furthermore,tumors create an immunosuppressive microenvironment via immunosuppressive cells and secrete molecules that hinder immune cell and immune modulator infiltration or induce immune cell malfunction.To address these challenges,smart drug delivery systems(SDDSs)have been developed to overcome tumor cell resistance to immunomodulators,restore or boost immune cell activity,and magnify immune responses.To combat resistance to small molecules and monoclonal antibodies,SDDSs are used to co-deliver numerous therapeutic agents to tumor cells or immunosuppressive cells,thus increasing the drug concentration at the target site and improving efficacy.Herein,we discuss how SDDSs overcome drug resistance during cancer immunotherapy,with a focus on recent SDDS advances in thwarting drug resistance in immunotherapy by combining immunogenic cell death with immunotherapy and reversing the tumor immunosuppressive microenvironment.SDDSs that modulate the interferon signaling pathway and improve the efficacy of cell therapies are also presented.Finally,we discuss potential future SDDS perspectives in overcoming drug resistance in cancer immunotherapy.We believe that this review will contribute to the rational design of SDDSs and development of novel techniques to overcome immunotherapy resistance.

Acid-switchable nanoparticles induce self-adaptive aggregation for enhancing antitumor immunity of natural killer cells

Deficiency of natural killer(NK)cells shows a significant impact on tumor progression and failure of immunotherapy.It is highly desirable to boost NK cell immunity by upregulating active receptors and relieving the immunosuppressive tumor microenvironment.Unfortunately,mobilization of NK cells is hampered by poor accumulation and short retention of drugs in tumors,thus declining antitumor efficiency.Herein,we develop an acid-switchable nanoparticle with self-adaptive aggregation property for co-delivering galunisertib and interleukin 15(IL-15).The nanoparticles induce morphology switch by a decomposition-metal coordination cascade reaction,which provides a new methodology to trigger aggregation.It shows self-adaptive size-enlargement upon acidity,thus improving drug retention in tumor to over 120 h.The diameter of agglomerates is increased and drug release is effectively promoted following reduced p H values.The nanoparticles activate both NK cell and CD8+T cell immunity in vivo.It significantly suppresses CT26 tumor in immune-deficient BALB/c mice,and the efficiency is further improved in immunocompetent mice,indicating that the nanoparticles can not only boost innate NK cell immunity but also adaptive T cell immunity.The approach reported here provides an innovative strategy to improve drug retention in tumors,which will enhance cancer immunotherapy by boosting NK cells.

Recent advances in developing active targeting and multi-functional drug delivery systems via bioorthogonal chemistry

Bioorthogonal chemistry reactions occur in physiological conditions without interfering with normal physiological processes.Through metabolic engineering,bioorthogonal groups can be tagged onto cell membranes,which selectively attach to cargos with paired groups via bioorthogonal reactions.Due to its simplicity,high efficiency,and specificity,bioorthogonal chemistry has demonstrated great application potential in drug delivery.On the one hand,bioorthogonal reactions improve therapeutic agent delivery to target sites,overcoming off-target distribution.On the other hand,nanoparticles and biomolecules can be linked to cell membranes by bioorthogonal reactions,providing approaches to developing multi-functional drug delivery systems(DDSs).In this review,we first describe the principle of labeling cells or pathogenic microorganisms with bioorthogonal groups.We then highlight recent breakthroughs in developing active targeting DDSs to tumors,immune systems,or bacteria by bioorthogonal chemistry,as well as applications of bioorthogonal chemistry in developing functional bio-inspired DDSs(biomimetic DDSs,cell-based DDSs,bacteria-based and phage-based DDSs)and hydrogels.Finally,we discuss the difficulties and prospective direction of bioorthogonal chemistry in drug delivery.We expect this review will help us understand the latest advances in the development of active targeting and multi-functional DDSs using bioorthogonal chemistry and inspire innovative applications of bioorthogonal chemistry in developing smart DDSs for disease treatment.

Versatile biomimetic nanomedicine for treating cancer and inflammation disease

Nanosized drug delivery systems(NDDSs)have emerged as a powerful tool to optimize drug delivery in complex diseases,including cancer and inflammation.However,the therapeutic effect of NDDSs is still far from satisfactory due to their poor circulation time,low delivery efficiency,and innate toxicity.Fortunately,biomimetic approaches offer new opportunities to develop nanomedicine,which is derived from a variety of native biomolecules including cells,exosomes,bacteria,and so on.Since inheriting the superior biocompatibility and versatile functions of natural materials,biomimetic nanomedicine can mimic biological processes,prolong blood circulation,and lower immunogenicity,serving as a desired platform for precise drug delivery for treating cancer and inflammatory disease.In this review,we outline recent advances in biomimetic NDDSs,which consist of two concepts:biomimetic exterior camouflage and bioidentical molecule construction.We summarize engineering strategies that further functionalized current biomimetic NDDSs.A series of functional biomimetic NDDSs created by our group are introduced.We conclude with an outlook on remaining challenges and possible directions for biomimetic NDDSs.We hope that better technologies can be inspired and invented to advance drug delivery systems for cancer and inflammation therapy.

Gold nanomaterials for treatment of metastatic cancer

Nanomedicine has shown good potentials for cancer diagnosis and treatment since the last decades. Among the various nanoparticles exploited for cancer management so far, gold nanomaterials(e.g., spherical gold nanoparticles and gold nanorods)were extensively investigated due to their unique chemo-physical properties. We herein summarize the emerging application and discuss the challenges of using gold nanomaterials for therapy of metastatic cancer.

Light-controllable charge-reversal nanoparticles with polyinosinic-polycytidylic acid for enhancing immunotherapy of triple negative breast cancer

Nucleic acid drugs are highly applicable for cancer immunotherapy with promising therapeutic effects, while targeting delivery of these drugs to disease lesions remains challenging. Cationic polymeric nanoparticles have paved the way for efficient delivery of nucleic acid drugs, and achieved stimuli-responsive disassembly in tumor microenvironment(TME). However, TME is highly heterogeneous between individuals, and most nanocarriers lack active-control over the release of loaded nucleic acid drugs, which will definitely reduce the therapeutic efficacy. Herein, we have developed a lightcontrollable charge-reversal nanoparticle(LCCN) with controlled release of polyinosinic-polycytidylic acid [Poly(I:C)] to treat triple negative breast cancer(TNBC) by enhanced photodynamic immunotherapy. The nanoparticles keep suitably positive charge for stable loading of Poly(I:C), while rapidly reverse to negative charge after near-infrared light irradiation to release Poly(I:C). LCCN-Poly(I:C) nanoparticles trigger effective phototoxicity and immunogenic cell death on 4 T1 tumor cells, elevate antitumor immune responses and inhibit the growth of primary and abscopal 4 T1 tumors in mice. The approach provides a promising strategy for controlled release of various nucleic acid-based immune modulators, which may enhance the efficacy of photodynamic immunotherapy against TNBC.