Shaping the “hot” immunogenic tumor microenvironment by nanoparticles co‐delivering oncolytic peptide and TGF‐β1 siRNA for boosting checkpoint blockade therapy

Abstract

Induction of potent immune responses toward tumors remains challenging in cancer immunotherapy, in which it only showed benefits in a minority of patients with “hot” tumors, which possess pre‐existing effector immune cells within the tumor. In this study, we proposed a nanoparticle‐based strategy to fire up the “cold” tumor by upregulating the components associated with T and NK cell recruitment and activation and suppressing TGF‐β1 secretion by tumor cells. Specifically, LTX‐315, a first‐in‐class oncolytic cationic peptide, and TGF‐β1 siRNA were co‐entrapped in a polymer‐lipid hybrid nanoparticle comprising PLGA, DSPE‐mPEG, and DSPE‐PEG‐conjugated with cRGD peptide (LTX/siR‐NPs). The LTX/siR‐NPs showed significant inhibition of TGF‐β1 expression, induction of type I interferon release, and triggering immunogenic cell death (ICD) in treated tumor cells, indicated via the increased levels of danger molecules, an in vitro setting. The in vivo data showed that the LTX/siR‐NPs could effectively protect the LTX‐315 peptide from degradation in serum, which highly accumulated in tumor tissue. Consequently, the LTX/siR‐NPs robustly suppressed TGF‐β1 production by tumor cells and created an immunologically active tumor with high infiltration of antitumor effector immune cells. As a result, the combination of LTX/siR‐NP treatment with NKG2A checkpoint inhibitor therapy remarkably increased numbers of CD8+NKG2D+ and NK1.1+NKG2D+ within tumor masses, and importantly, inhibited the tumor growth and prolonged survival rate of treated mice. Taken together, this study suggests the potential of the LTX/siR‐NPs for inflaming the “cold” tumor for potentiating the efficacy of cancer immunotherapy.

Engineering nanomedicines for immunogenic eradication of cancer cells: Recent trends and synergistic approaches

“…Moreover, the combination resulted in generating long-term immune memory which enabled resistance to re-challenged B16F10 cells compared to mice treated with free LTX-315 which developed tumor relapse. In another approach, cRGD-coupled polymer-lipid hybrid NPs co-delivering LTX-315 peptide and TGF- β 1 siRNA were designed 82 . The released DAMPs were enhanced in LTX NP-treated 4T1 tumor cells including translocation of CRT, and the release of ATP and HMGB1.…”

Advanced technologies for biomedical applications by emerging researchers in Asia‐Pacific

“…17 Phung and colleagues prepared polymer-lipid hybrid nanoparticles that co-encapsulated LTX-315, a pioneering oncolytic cationic peptide, and TGF-β1 siRNA to enhance the effectiveness of cancer immunotherapy. 18 Cai et al prepared gold nanoparticles conjugated with internalizing-RGD peptide and loaded with siCDK7 for inducing immunotherapeutic responses against lung cancer. 19 Kim et al prepared piperazine-based ionizable lipid nanoparticles for the targeted delivery of mRNA to fibrotic lungs.…”

“…Zhu et al designed various nanobodies of anti‐vascular endothelial growth factor (VEGF) proteins for sustained release of proteins, which provides a novel approach for chronic intravitreal administration of anti‐VEGF proteins 17 . Phung and colleagues prepared polymer‐lipid hybrid nanoparticles that co‐encapsulated LTX‐315, a pioneering oncolytic cationic peptide, and TGF‐β1 siRNA to enhance the effectiveness of cancer immunotherapy 18 . Cai et al prepared gold nanoparticles conjugated with internalizing‐RGD peptide and loaded with siCDK7 for inducing immunotherapeutic responses against lung cancer 19 .…”

Approved Nanomedicine against Diseases

“…Nanomedicine emerged to overcome these problems and has made significant progress. Nanomedicine improves the pharmacokinetic behavior of drugs and reduces toxicity by improving drug solubility, altering biodistribution, and controlling the release [ 5 ]. The large surface area of nanoparticles offers an enhanced interaction with cells and effectively increases the intracellular drug concentration [ 6 ].…”