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Combination therapies using checkpoint inhibitors with immunostimulatory agonists have attracted great attention due to their synergistic therapeutic effects for cancer treatment. However, such combination immunotherapies require specific timing of doses to show sufficient antitumor efficacy. Sequential treatment usually requires multiple administrations of the individual drugs at specific time points, thus increasing the complexity of the drug regimen and compromising patient compliance. Here, we introduce an injectable porous silicon microparticle (pSiMP) for combination cancer immunotherapy where its multilayered nanopore structure was electrochemically programmed to achieve release of three distinct immunomodulatory drugs in the right sequence at the desired time. We find the optimal sequential treatment timeline of stimulator of interferon genes (STING) agonist, anti-OX40 antibody (aOX40), and anti-PD-1 antibody (aPD-1) for immunosuppressive tumors. We show that a single intratumoral injection of a cocktail of release-programmed pSiMPs coloaded with each antibody and a STING agonist significantly suppresses the tumor growth compared to conventional treatment involving sequential bolus injections, or an injection of pSiMPs configured to release all drugs at the same time, with no delay. With the timely release of immunomodulatory drugs, the programmable pSiMPs offer an effective treatment strategy for combination immunotherapy. 

Abstract BackgroundBasic fibroblast growth factor (bFGF) is one of the critical components accelerating angiogenesis and tissue regeneration by promoting the migration of dermal fibroblasts and endothelial cells associated with matrix formation and remodeling in wound healing process. However, clinical applications of bFGF are substantially limited by its unstable nature due to rapid decomposition under physiological microenvironment. ResultsIn this study, we present the bFGF-loaded human serum albumin nanoparticles (HSA-bFGF NPs) as a means of enhanced stability and sustained release platform during tissue regeneration. Spherical shape of the HSA-bFGF NPs with uniform size distribution (polydispersity index < 0.2) is obtainedviaa simple desolvation and crosslinking process. The HSA-bFGF NPs securely load and release the intact soluble bFGF proteins, thereby significantly enhancing the proliferation and migration activity of human dermal fibroblasts. Myofibroblast-related genes and proteins were also significantly down-regulated, indicating decrease in risk of scar formation. Furthermore, wound healing is accelerated while achieving a highly organized extracellular matrix and enhanced angiogenesis in vivo. ConclusionConsequently, the HSA-bFGF NPs are suggested not only as a delivery vehicle but also as a protein stabilizer for effective wound healing and tissue regeneration. 

Abstract Traumatic brain injury (TBI) impacts millions of people globally, however currently there are no approved therapeutics that address long‐term brain health. In order to create a technology that is relevant for siRNA delivery in TBI after systemic administration, sub‐100 nm nanoparticles with rolling circle transcription (RCT) are synthesized and isolated in order improve payload delivery into the injured brain. Unlike conventional RCT‐based RNA particles, in this method, sub‐100 nm RNA nanoparticles (RNPs) are isolated. To enhance RNP pharmacokinetics, RNPs are synthesized with modified bases in order to graft polyethylene glycol (PEG) to the RNPs. PEGylated RNPs (PEG‐RNPs) do not significantly impact their knockdown activity in vitro and lead to longer blood half‐life after systemic administration and greater accumulation into the injured brain in a mouse model of TBI. In order to demonstrate RNA interference (RNAi) activity of RNPs, knockdown of the inflammatory cytokine TNF‐α in injured brain tissue after systemic administration of RNPs in a mouse model of TBI is demonstrated. In summary, small sub‐100 nm multimeric RNA nanoparticles are synthesized and isolated that can be modified using accessible chemistry in order to create a technology suitable for systemic RNAi therapy for TBI. 

Abstract Nonlinear microscopy provides excellent depth penetration and axial sectioning for 3D imaging, yet widespread adoption is limited by reliance on expensive ultrafast pulsed lasers. This work circumvents such limitations by employing rare‐earth doped upconverting nanoparticles (UCNPs), specifically Yb³⁺/Tm³⁺co‐doped NaYF₄nanocrystals, which exhibit strong multimodal nonlinear optical responses under continuous‐wave (CW) excitation. These UCNPs emit multiple wavelengths at UV (λ ≈ 450 nm), blue (λ ≈ 450 nm), and NIR (λ ≈ 800 nm), whose intensities are nonlinearly governed by excitation power. Exploiting these properties, multi‐colored nonlinear emissions enable functional imaging of cerebral blood vessels in deep brain. Using a simple optical setup, high resolution in vivo 3D imaging of mouse cerebrovascular networks at depths up to 800 µmm is achieved, surpassing performance of conventional imaging methods using CW lasers. In vivo cerebrovascular flow dynamics is also visualized with wide‐field video‐rate imaging under low‐powered CW excitation. Furthermore, UCNPs enable depth‐selective, 3D‐localized photo‐modulation through turbid media, presenting spatiotemporally targeted light beacons. This innovative approach, leveraging UCNPs' intrinsic nonlinear optical characteristics, significantly advances multimodal nonlinear microscopy with CW lasers, opening new opportunities in bio‐imaging, remote optogenetics, and photodynamic therapy.