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[Display omitted] • Continuous assembly strategy gives more functions. • Proper initiation of self-assembly maximizes the therapeutic potential of the drug. • Accurate photoacoustic apoptosis monitoring optimized the therapeutic protocol. • A simpler versatile nanoagent. Although considerable progress has been made in nanomedicine, it is still of great significance for nanomedicine machines with natural targeting, diverse functions, maximum drug utilization, and outstanding performance. In this work, a simple small molecule chimeric peptide with the capability of sequential two-step self-assembly was developed. This chimeric peptide could be self-assembled into larger nanoparticles from smaller nanoparticles at tumor extracellular acidic microenvironment and further aggregated in apoptotic tumor cells mediated by photodynamic therapy. In addition to the nanostructure changes, the increasing of size could accelerate cell internalization and tumor accumulation of chimeric peptide for better photodynamic therapy. And the aggregation in the apoptotic cell could enhance the photothermal effect and photoacoustic signal of chimeric peptide for further photothermal therapy and photoacoustic imaging of tumor apoptosis. Both in vitro and in vivo studies demonstrated that these self-assembly behaviors endowed chimeric peptide with well tumor accumulation, preferable tumor suppression, and precise therapeutic evaluation, which should provide a new way for the construction of efficient theranostic agent based on chimeric peptides. [ABSTRACT FROM AUTHOR]

Poly(ethylene glycol) (PEG) is widely utilized as a hydrophilic coating to extend the circulation time and improve the tumor accumulation of polymeric micelles. Nonetheless, PEGylated micelles often activate complement proteins, leading to accelerated blood clearance and negatively impacting drug efficacy and safety. Here, we have crafted amphiphilic block copolymers that merge hydrophilic sulfoxide-containing polymers (psulfoxides) with the hydrophobic drug 7-ethyl-10-hydroxylcamptothecin (SN38) into drug-conjugate micelles. Our findings show that the specific variant, PMSEA-PSN38 micelles, remarkably reduce protein fouling, prolong blood circulation, and improve intratumoral accumulation, culminating in significantly increased anti-cancer efficacy compared with PEG-PSN38 counterpart. Additionally, PMSEA-PSN38 micelles effectively inhibit complement activation, mitigate leukocyte uptake, and attenuate hyperactivation of inflammatory cells, diminishing their ability to stimulate tumor metastasis and cause inflammation. As a result, PMSEA-PSN38 micelles show exceptional promise in the realm of anti-metastasis and significantly abate SN38-induced intestinal toxicity. This study underscores the promising role of psulfoxides as viable PEG substitutes in the design of polymeric micelles for efficacious anti-cancer drug delivery. This study emphasizes PMSEA's potential as a sulfoxide-containing polymer for anti-cancer drug delivery, offering an alternative to PEG in constructing polymeric prodrug micelles efficiently. [Display omitted] • Sulfoxide-containing polymer PMeSEA presents a promising alternative to PEG. • Micelles grafted with PMeSEA successfully diminish complement system activation. • Reducing complement activation enhances the antitumor activity of PMeSEA-micelles. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages play pivotal roles in tumor progression and metastasis. Macrophage-mediated clearance of apoptotic cells (efferocytosis) supports inflammation resolution, contributing to immune evasion in colorectal cancers. To reverse this immunosuppressive process, we propose a readily translatable RNA therapy to selectively inhibit macrophage-mediated efferocytosis in tumor microenvironment. A clinically approved lipid nanoparticle platform (LNP) is employed to encapsulate siRNA for the phagocytic receptor MerTK (siMerTK), enabling selective MerTK inhibition in the diseased organ. Decreased MerTK expression in tumor-associated macrophages results in apoptotic cell accumulation and immune activation in tumor microenvironment, leading to suppressed tumor growth and better survival in both liver and peritoneal metastasis models of colorectal cancers. siMerTK delivery combined with PD-1 blockade further produces enhanced antimetastatic efficacy with reactivated intratumoral immune milieu. Collectively, LNP-based siMerTK delivery combined with immune checkpoint therapy may present a feasible modality for metastatic colorectal cancer therapy. [Display omitted] • MerTK is a promising therapeutic target in colorectal cancer liver metastasis. • LNPsencapsulating siMerTK induce efferocytosis blockade for reprogramming tumor immune microenvironment. • Modulation of macrophage-mediated efferocytosis improves the therapy response of checkpoint blockade in metastatic colorectal cancer. [ABSTRACT FROM AUTHOR]

Capsaicin is a natural non-toxic small molecular organic substance, which is often used clinically to reduce inflammation and pain. Here, we report an acid-responsive CaCO 3 nanoparticle loaded with capsaicin that can specifically activate TRPV1 channels and trigger tumor calcium ion therapy. The excellent acid responsiveness of calcium carbonate enables it to precisely target the tumor sites. The released capsaicin can specifically activate TRPV1 channel, overloading the intracellular calcium ion concentration and causing cell apoptosis, which provides a new safer and cheaper treatment. We proved that the naturalness and non-toxicity of capsaicin make the CaCO 3 @CAP nanoparticles have excellent biocompatibility, which has good development prospects and clinical application potential. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) brings excellent treatment outcome while also causing poor tumor microenvironment and prognosis due to the uncontrolled oxygen consumption. To solve this issue, a novel PDT strategy, oxygenated PDT (maintain the tumor oxygenation before and after PDT) was carried out by a tumor and apoptosis responsive photoactivity conversion nanocomposite (MPPa-DP). Under physiological conditions, this nanocomposite has a low photoactivity. While at H 2 O 2 -rich tumor microenvironment, the nanocomposite could react with overexpressed H 2 O 2 to produce O 2 and release high photoactivity chimeric peptide PPa-DP for oxygenated tumor and PDT. Importantly, when the PDT mediates cell apoptosis, the photoactivity of PPa-DP be effectively quenched and the O 2 consumption appeared retard, which avoided further consumption of residual O 2 on apoptotic cells. In vitro and vivo studies revealed that this nanocomposite could efficiently change photoactivity, reasonable control O 2 consumption and increase residual O 2 content of tumor after PDT. [ABSTRACT FROM AUTHOR]

• Acidity-triggered charge-reversed AuNPs have been prepared successfully. • Charge-reversed AuNPs accumulate on the bacterial infection sites. • Aggregated AuNPs exhibit excellent antibacterial activity under NIR radiation. • Charge-reversed AuNPs precisely kill bacteria without damaging healthy tissues. Precisely striking the bacterially infected site and avoiding damage to healthy tissues is vital for bacterial infection therapy. Herein, an intelligent antibacterial platform that triggers the aggregation of gold nanoparticles (AuNPs) on bacterial surface based on the acidic environment of bacterial infection was developed. Also, the AuNPs functionalized with an acidity-triggered moiety (Pep-DA) exhibited a charge-convertible properties to target bacterial infection sites. The positively charged acidity-triggered AuNPs endowed the AuNPs aggregate on negatively charged bacterial surface in the infected site rather than in healthy tissues, achieving the threshold to interparticle plasmonic coupling effect among AuNPs, and killing bacteria accurately under NIR irradiation light. This acidity-triggered aggregation strategy provides an excellent therapeutic mode for treating focal bacterial infections with no critical damage to healthy tissues. [ABSTRACT FROM AUTHOR]