M1-polarized macrophage-derived cellular nanovesicle-coated lipid nanoparticles for enhanced cancer treatment through hybridization of gene therapy and cancer immunotherapy

Optimum genetic delivery for modulating target genes to diseased tissue is a major obstacle for profitable gene therapy.Lipid nanoparticles(LNPs),considered a prospective vehicle for nucleic acid delivery,have demonstrated efficacy in human use during the COVID-19 pandemic.This study introduces a novel biomaterial-based platform,M1-polarized macrophage-derived cellular nanovesicle-coated LNPs(M1-C-LNPs),specifically engineered for a combined gene-immunotherapy approach against solid tumor.The dual-function system of M1-C-LNPs encapsulates Bcl2-targeting siRNA within LNPs and immune-modulating cytokines within M1 macrophage-derived cellular nanovesicles(M1-NVs),effectively facilitating apoptosis in cancer cells without impacting T and NK cells,which activate the intratumoral immune response to promote granule-mediating killing for solid tumor eradication.Enhanced retention within tumor was observed upon intratumoral administration of M1-C-LNPs,owing to the presence of adhesion molecules on M1-NVs,thereby contributing to superior tumor growth inhibition.These findings represent a promising strategy for the development of targeted and effective nanoparticle-based cancer genetic-immunotherapy,with significant implications for advancing biomaterial use in cancer therapeutics.

Macrophage-derived extracellular vesicles regulate skeletal stem/progenitor Cell lineage fate and bone deterioration in obesity

Obesity-induced chronic inflammation exacerbates multiple types of tissue/organ deterioration and stem cell dysfunction;however,the effects on skeletal tissue and the underlying mechanisms are still unclear.Here,we show that obesity triggers changes in the microRNA profile of macrophage-secreted extracellular vesicles,leading to a switch in skeletal stem/progenitor cell(SSPC)differentiation between osteoblasts and adipocytes and bone deterioration.Bone marrow macrophage(BMM)-secreted extracellular vesicles(BMM-EVs)from obese mice induced bone deterioration(decreased bone volume,bone microstructural deterioration,and increased adipocyte numbers)when administered to lean mice.Conversely,BMM-EVs from lean mice rejuvenated bone deterioration in obese recipients.We further screened the differentially expressed microRNAs in obese BMM-EVs and found that among the candidates,miR-140(with the function of promoting adipogenesis)and miR-378a(with the function of enhancing osteogenesis)coordinately determine SSPC fate of osteogenic and adipogenic differentiation by targeting the Pparα-Abca1 axis.BMM miR-140 conditional knockout mice showed resistance to obesity-induced bone deterioration,while miR-140 overexpression in SSPCs led to low bone mass and marrow adiposity in lean mice.BMM miR-378a conditional depletion in mice led to obesity-like bone deterioration.More importantly,we used an SSPC-specific targeting aptamer to precisely deliver miR-378a-3p-overloaded BMM-EVs to SSPCs via an aptamer-engineered extracellular vesicle delivery system,and this approach rescued bone deterioration in obese mice.Thus,our study reveals the critical role of BMMs in mediating obesity-induced bone deterioration by transporting selective extracellular-vesicle microRNAs into SSPCs and controlling SSPC fate.