Nanomedicine-based cancer immunotherapy: recent trends and future perspectives

Purpose: Cancer immunotherapy has shown efficacy but is limited by serious adverse effects, nonspecific inflammation, and challenges in spatiotemporal control of immune responses. Nanomedicine and functionalized nanosystems offer programmable pharmacokinetics, co-delivery of immunomodulators, and targeted delivery, potentially improving immunotherapy outcomes.

Hypothesis: No formal experimental hypothesis. Central thesis: combining cancer immunotherapy with functionalized nanosystems—such as stimuli-responsive NPs, CRISPR-Cas nanoparticles, core-shell NPs, biomimetic NPs, and CAR-T cell-enabling nanotechnologies—can enhance efficacy, reduce toxicity, and enable synergistic combination therapies.

Aims: Review recent trends in nanomedicine-based cancer immunotherapy. - Focus on immune checkpoint inhibitors and nanomedicine. - Discuss CRISPR-Cas nanoparticles in cancer immunotherapy. - Summarize combination cancer immunotherapy with core-shell nanoparticles. - Review biomimetic nanoparticles for cancer immunotherapy. - Examine CAR-T cells and cancer nanoimmunotherapy. - Discuss challenges and future perspectives, including lyophilized CAR-T DNA nanocomplexes.

Delivery system: Nanoparticles: mesoporous silica NPs, antigen-capturing NPs (AC-NPs), nanoscale immunoconjugates (NICs), nanoscale coordination polymer (NCP) core-shell particles, poly(beta-amino ester) (PBAE) NPs, dual immunotherapy nanoparticles (DINPs), nanoscale metal-organic frameworks (nMOFs), cationic lipid-assisted PEG-b-PLGA NPs (CLANs), pH-responsive NPs, human serum albumin (HSA) NPs, arginine-coated gold NPs, liposomes, multilamellar liposomal vesicles (cMLVs), core-shell NPs (PLGA, NCP, zinc pyrophosphate, Fe₃O₄/ZnO, CaCO₃, upconversion), biomimetic NPs (cancer cell membrane, RBC membrane), and CAR-T DNA nanocomplexes. - Payloads: CRISPR-Cas9 components (plasmid DNA, guide RNA, Cas9 protein), immune checkpoint inhibitors (anti-PD-1, anti-PD-L1, anti-CTLA-4 antibodies or nanobodies), STING agonists (cyclic dinucleotides), siRNA (e.g., against lactate dehydrogenase A, PD-L1, STAT3, SOCS1, CD73, A20, CCR2, VEGF, CD47), plasmid DNA (IL-2, EGFRvIII-CAR), chemotherapeutics (oxaliplatin, gemcitabine, paclitaxel, doxorubicin), photosensitizers (pyrolipid, indocyanine green, chlorin e6, pheophorbide A), and immunomodulators (resiquimod, α-GalCer). - Targeting/functionalization: cell-specific promoters (CD68 for macrophages/monocytes), tumor-targeting peptides (iRGD, SP94), antibodies, aptamers, cancer cell membranes, RBC membranes, and pH-responsive deshielding.

Approach: Review of preclinical and clinical literature. In vitro models include Jurkat cells, B16 melanoma cells, breast cancer cells, and 3D culture models of breast cancer liver metastasis. In vivo models include B16F10 melanoma, breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma, glioblastoma, and bilateral syngeneic mouse tumor models. Clinical context includes a phase I trial of PD-1-deficient engineered T cells with CRISPR/Cas9 in advanced non-small cell lung cancer, and approved anti-CD19 CAR-T therapies (UCART19) for relapsed/refractory hematological cancers.

Key methods: Tumor growth inhibition, survival, cure rate, and abscopal effects. - Immune cell profiling: CD8⁺ T cell infiltration, CD4⁺/Treg and CD8⁺/Treg ratios, NK cells, dendritic cell activation, macrophage polarization (M1/M2). - Cytokine secretion and immunogenic cell death markers. - Gene editing efficiency: knockout of Ntn1, SIRP-α, RICTOR, Cdk5, PD-L1. - Biodistribution, blood-brain barrier penetration, and systemic toxicity. - Imaging and tracking of dendritic cell migration. - Mathematical modeling of macrophage ratios in combination therapy.

Key results: Antigen-capturing NPs (AC-NPs) plus αPD-1 improved cure rate by 20% in B16F10 melanoma, expanded CD8⁺ cytotoxic T cells, and increased CD4⁺/Treg and CD8⁺/Treg ratios. - Cationic lipid-assisted PEG-b-PLGA NPs (CLANs) achieved macrophage/monocyte-specific Cas9 expression and Ntn1 knockout in vivo, with limited editing in non-target immune cells. - pH-responsive NPs co-delivering CRISPR-Cas9 and paclitaxel blocked PD1/PD-L1, attenuated tumor PD-L1 via Cdk5 knockout, reduced Tregs, activated dendritic cells, repolarized M2 to M1 macrophages, and induced immunogenic cell death. - Arginine-coated gold NPs co-delivering guide RNA and Cas9 protein knocked out SIRP-α in macrophages, drastically enhancing phagocytic potential. - Liposomal CRISPR delivery silenced RICTOR, polarized M2 to M1 macrophages, and potentiated mesoporous albumin-bound paclitaxel (MSV-nab-PTX) in a 3D breast cancer liver metastasis model. - Core-shell PLGA NPs delivering gambogic acid, heparin, and CpG-ODN sequentially killed tumor cells, inhibited angiogenesis, and stimulated Th1 antitumor immunity. - NCP core-shell NPs carrying oxaliplatin and pyrolipid combined chemotherapy and photodynamic therapy, induced immunogenic cell death, and regressed primary and distant tumors with anti-PD-L1 therapy. - Biomimetic cancer cell membrane-coated PLGA NPs interrupted cancer cell–fibroblast crosstalk, prevented metastasis, migrated to lymph nodes, and stimulated cytotoxic T-cell responses. - CAR-T cells secreting PD-1-blocking scFv improved antitumor activity in syngeneic and xenogeneic mouse models of PD-L1 hematological and solid tumors. - IL-15 superagonist nanogel backpacked onto CAR-T cells selectively expanded T cells, increased tumor clearance, and avoided toxicity. - CAR-T therapy showed ~80% remission rates in hematological cancers, especially non-Hodgkin’s lymphoma and acute lymphoblastic leukemia.

Interpretation: Nanomedicine-based cancer immunotherapy enables spatiotemporal control, co-delivery of immunomodulators, and combination with conventional therapies to achieve synergistic antitumor effects. CRISPR-Cas NPs, core-shell NPs, biomimetic NPs, and CAR-T nanoimmunotherapy are promising strategies. Future directions include lyophilized CAR-T DNA nanocomplexes for improved efficiency and cost-effectiveness, and surface-engineered multifunctional magnetic nanosystems for image-guided therapy.

Limitations: Review article; no primary data. - Many studies remain preclinical; clinical translation is limited. - Challenges include off-target gene editing, immune-related toxicity, manufacturing complexity, storage requirements, high costs, tumor heterogeneity, and variable patient responses. - CRISPR-Cas delivery faces immunogenicity risks with viral vectors and inefficient non-viral delivery. - CAR-T therapy limitations: severe toxicities, restricted trafficking/infiltration into solid tumors, suboptimal in vivo persistence, antigen escape, and manufacturing issues. - Biomimetic NP scale-up and quality control remain challenging. - Need for robust quality control and standardized protocols for clinical translation.